bims-musmir 2026-03-01 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–03–01
twenty-two papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.
Entropy of Muscle Fiber Histology Predicts Mobility in Older Adults: The Study of Muscle, Mobility, and Aging.
High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
A Novel Mouse Model to Identify Antigen-Specific Immune Responses in Pancreatic Cancer Cachexia.
Dysbiosis of the enteric DNA virome correlates with the development of cachexia in a murine Lewis lung carcinoma (LLC) model.
Tumor-Derived LIF Promotes GDF15-Driven Cachexia and Adverse Outcomes in Gastric Cancer.
Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.
A network-based atlas of human skeletal muscle aging.
Role of mitochondrial dysfunction in muscle wasting in cancer cachexia: a narrative review.
TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo.
Circulating Inflammatory and Mitochondrial Biomarkers Associated with Cachexia in Advanced Non-Small Cell Lung Cancer.
Repeated Disuse Atrophy Imprints a Molecular Memory in Skeletal Muscle: Transcriptional Resilience in Young Adults and Susceptibility in Aged Muscle.
AUF1 therapy blocks atrophy, promotes regeneration, re-innervation and strength for severe muscle injury.
The Muscle Function Deficit Concept and Inflammaging.
Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
Translational studies of chronic supplementation with a mitochondria-targeted antioxidant to improve physical function with ageing.
The Effects of ACTH and Dexamethasone on the Transcriptomic Profile of the Rat Adrenal Gland: An In Vivo Study.
C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.
Nerve, muscle and adiposity: Associations with gait speed across adulthood in the Baltimore Longitudinal Study of Aging.
Myonuclear loss, rather than senescent myonuclei, associates with fiber type-specific atrophy in aging human skeletal muscle.
Select Small Non-Coding RNAs Are Determinants of Survival in Older Adults.
Nerve Injury-Induced Protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.

bioRxiv. 2026 Feb 13. pii: 2026.02.12.705530. [Epub ahead of print]

Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.

Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Martin Picard, Abbey-Gale Mannings, Michael Cohen, Dennis Wolan, Terence E Ryan, Russell T Hepple.

Background: Skeletal muscle in wasting conditions often exhibits a common set of phenotypes that include atrophy, mitochondrial respiratory dysfunction, and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. Mitochondria are frequently implicated in driving muscle pathology in these conditions, although which aspects of mitochondrial function are most relevant is poorly understood.
Methods: To address this gap, we focused on mitochondrial permeability transition (mPT), a well-established pathological mechanism in ischemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle. We performed a broad assessment of the consequences of mPT in skeletal muscle, focusing on features that are common in wasting conditions. We then tested whether tumor-host factors could promote mPT and compared differentially expressed genes (DEGs) with mPT and a mouse model of pancreatic cancer cachexia.
Results: Inducing mPT in mouse skeletal muscle bundles in a Ca 2+ retention capacity assay progressively altered mitochondrial morphology, beginning with cristae swirling and condensation, progressing to mitochondrial cristae displacement, and culminating in breach of the outer mitochondrial membrane; features that are common in wasting conditions. Inducing mPT with Bz423 in single mouse muscle fibers increased mROS and Caspase 3 (Casp3) activity and was prevented by inhibitors of mPT, mROS or Casp3. Incubating single muscle fibers with Bz423 for 24 h reduced fiber diameter by ∼20% which was prevented by inhibiting mPT, mROS, or Casp3. Inducing mPT caused a complex I-specific mitochondrial respiratory impairment and increased co-localization of lysosomes with mitochondria. Inducing mPT also fragmented the AChR cluster at the muscle endplate and was prevented by inhibiting mPT or Casp3. The Ca 2+ threshold for mPT and mitochondrial calcein colocalization were reduced by pancreatic tumor-conditioned media in skeletal muscle or C2C12 myoblasts, respectively, and these effects were counteracted by mPT inhibition or cyclophilin D knockout. Finally, there was significant overlap between the transcriptome of mPT and that seen in diaphragm muscle in a mouse model of pancreatic cancer cachexia, particularly during the muscle wasting phase.
Conclusions: We conclude that inducing mPT in skeletal muscle recapitulates muscle phenotypes common with muscle wasting conditions like cachexia. Furthermore, mPT is engaged by tumor-host factors and had significant overlap with DEGs seen during the muscle wasting phase in a mouse model of pancreatic cancer cachexia, warranting further investigation of mPT as a therapeutic target.

DOI: https://doi.org/10.64898/2026.02.12.705530
Aging Cell. 2026 Mar;25(3): e70421

Entropy of Muscle Fiber Histology Predicts Mobility in Older Adults: The Study of Muscle, Mobility, and Aging.

Namki Hong, Sang Wouk Cho, Alan A Cohen, Russell T Hepple, Paul M Coen, Bumsoo Ahn, Anne B Newman, Stephen B Kritchesky, Paul J Laurenti, Warren S Browner, Steven R Cummings.

  Entropy may play an underappreciated role in human aging, such as in skeletal muscle functional declines. Histologically, muscle appears increasingly disorganized with aging, with greater fiber size variability and fiber-type grouping. We tested the hypothesis that entropy is associated with reduced physical performance and muscle function, independent of muscle mass. We quantified a homeostatic dysregulation index of muscle (HDIM) as a proxy for entropy of muscle fiber disorganization based on cross-sectional images of vastus lateralis biopsies from 299 adults age 70 or older. HDIM was derived from three traits: fiber area diversity, fiber-type heterogeneity, and the mean of the shortest path lengths through adjacent fiber networks. HDIM derived from muscle fibers was highly correlated with Shannon entropy, a different measure of entropy of muscle fiber traits. Higher HDIM derived from participants was associated with slower 400-m walk speed, lower peak VO2, muscle power, and decreased maximum rate of oxidative phosphorylation by mitochondria in muscle. These findings suggest that muscle fibers accumulate entropy with aging which contributes to decline in physical performance, muscle power, and mitochondrial energetics, advancing the entropy framework in aging research.

Keywords:  aging; computer‐assisted; entropy; image processing; mobility limitation; muscles

DOI:  https://doi.org/10.1111/acel.70421
Am J Physiol Cell Physiol. 2026 Feb 21.

High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.

Brittany R Counts, Andrea Bonetto, Ho Lam Chan, Ernie D Au, Yanlin Jiang, Marion E Couch, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Teresa A Zimmers.

  High fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that obese patients might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus non-tumor bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD without tumors gained weight over the study, with obese HFD mice exhibiting low muscle mass with obesity at endpoint. Low fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, Interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-born inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.

Keywords:  Interleukin-6; cancer cachexia; high fat diet; obesity; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00545.2025
Cancers (Basel). 2026 Feb 11. pii: 587. [Epub ahead of print]18(4):

A Novel Mouse Model to Identify Antigen-Specific Immune Responses in Pancreatic Cancer Cachexia.

Ayushi Das, Debasmita Mukherjee, Liliana D'Alesio, Jessica Wedig, Hannah Lathrop, Maria Schmidt, Abigail Guenther, Morgan Kaiser, Jeon Varghese, Bryan Remaily, Samuel K Kulp, Jeovanna Lowe, Jill A Rafael-Fortney, Justin Thomas, Kyeongmin Kim, Adeoluwa Adeluola, Stacey Culp, Andrew Gunderson, Mitch A Phelps, Christopher C Coss, Thomas A Mace.

   BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) has a dismal five-year survival rate of 13% and is closely associated with cachexia. Cancer cachexia is a multifactorial syndrome characterized by irreversible wasting of skeletal muscles, fat loss and systemic inflammation. While cachexia is known to confer resistance to immune checkpoint inhibition in several cancers, the bidirectional relationship between cachexia and the immune system in PDAC remains unclear, necessitating the development of novel preclinical models. Our laboratory has characterized a novel pancreatic cancer cachexia model in C57BL/6J mice by utilizing the pancreatic cancer cell line called KPCL-4 derived from KPC-LSIY mice (KrasLSL-G12D/+Tp53LSL-R172H/+Pdx1-Cre/R26LSL-LSIY).
METHODS: KPCL-4 cells were orthotopically injected into the pancreas of male and female C57BL/6J mice and hallmarks of cachexia were assessed at endpoint by measurement of tumor weight, terminal tumor-adjusted body weight, skeletal muscle, adipose tissue, liver and spleen masses, proteolytic markers and grip strength. Plasma cytokine and chemokine concentrations were quantified by Luminex assay and high-dimensional flow cytometry was used to investigate changes in tumor-infiltrating immune populations.
RESULTS: We observed a sex bias in cachexia presentation despite similar tumor weights in male and female mice, whereby males exhibited a >5% decrease in terminal tumor-adjusted body weight (p < 0.001), >50% fat loss (p < 0.001), upregulation of proteolytic markers in skeletal muscles (p < 0.01) and reduction in skeletal muscle mass (p < 0.05), function (p < 0.01) and cross-sectional area (p < 0.0001) whereas females demonstrated conserved skeletal muscle mass with 33% fat loss (p < 0.05), reduction in muscle cross-sectional area (p < 0.0001) and splenomegaly (p < 0.01). While intra-tumoral immune populations did not exhibit sex-specific differences, plasma cytokine concentrations were differentially upregulated in males and females, suggesting functional differences in immune cells as potent drivers of sex bias in KPCL-4-driven cachexia.
CONCLUSIONS: The KPCL-4 orthotopic PDAC model exhibits prominent hallmarks of cachexia and serves as a novel platform for investigating the complex interplay between cancer cachexia and immunomodulation.

Keywords:  Immunotherapy; cachexia; immunomodulation; pancreatic cancer; preclinical models

DOI:  https://doi.org/10.3390/cancers18040587
Arch Virol. 2026 Feb 22. pii: 90. [Epub ahead of print]171(3):

Dysbiosis of the enteric DNA virome correlates with the development of cachexia in a murine Lewis lung carcinoma (LLC) model.

David Aciole Barbosa, Yara N L F de Maria, Fabiano B Menegidio, Regina Costa de Oliveira, Daniela L Jabes, Luiz R Nunes.

  Cachexia, a multifaceted wasting syndrome, profoundly impacts quality of life and survival rates in cancer patients. Gut inflammation is identified as a key player among the contributing factors for its development. Consequently, numerous studies have sought to characterize changes in gut microbiota of cachectic individuals, given the well-established roles of the gut microbiota in controlling and/or triggering both local and systemic inflammation in their hosts. Most of these investigations have applied mouse models of tumor-induced cachexia to show correlations between alterations in bacterial and fungal abundance in the digestive tract and the onset of cancer cachexia (CC). However, the role of viral dysbiosis in CC development remains unexplored. The present study aims to address this gap by characterizing the gut virome during the progression of murine cancer cachexia. Although our approach was limited to DNA viruses, our findings reveal that cachectic animals with Lewis lung carcinoma exhibited a subtle yet statistically significant modulation in composition (R2 = 0.17622; p = 0.05). A linear discriminant analysis effect size (LEfSe) analysis revealed that the dysbiosis observed in the gut virome of CC animals was mostly characterized by a significant enrichment in giant viruses of the family Phycodnaviridae (LDA score, 4.2582; p-value, 0.004; pwrapp, 0.9984) and significantly decreased populations of bacteriophages of the families Microviridae (LDA score, 4.3458; p-value, 0.0127; pwrapp, 0.9065) and Inoviridae (LDA score, 3.3028; p-value, 0.0017; pwrapp, 0.9992). This cachexia-associated viral dysbiosis shares similarities with virome alterations documented in other conditions linked to gut inflammation, including, ulcerative colitis, Crohn's disease, and Clostridioides difficile infection. These new insights suggest the potential contributions of viral communities to the pathophysiology of CC and other inflammation-driven diseases.

Keywords:  Bacteriophages; Cachexia; Giant viruses; Gut inflammation; Inoviridae; Metagenome; Microviridae; NGS; Phycodnaviridae; Virome

DOI:  https://doi.org/10.1007/s00705-026-06522-7
Cells. 2026 Feb 16. pii: 355. [Epub ahead of print]15(4):

Tumor-Derived LIF Promotes GDF15-Driven Cachexia and Adverse Outcomes in Gastric Cancer.

Cristina Di Giorgio, Nicola Natalizi, Maria Rosaria Sette, Martina Bordoni, Benedetta Sensini, Ginevra Lachi, Eleonora Giannelli, Francesca Paniconi, Luigi Cari, Silvia Marchianò, Michele Biagioli, Elva Morretta, Maria Chiara Monti, Bruno Charlier, Fabrizio Dal Piaz, Angela Zampella, Eleonora Distrutti, Luigina Graziosi, Annibale Donini, Stefano Fiorucci.

  Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and adipose tissue loss, systemic inflammation, and poor clinical outcomes, and represents a major unmet clinical need in gastric cancer. Growth Differentiation Factor 15 (GDF15) is a key mediator of cachexia-associated anorexia and tissue wasting; however, the upstream mechanisms regulating its expression in gastric cancer remain poorly defined. Leukemia Inhibitory Factor (LIF), a pleiotropic cytokine implicated in tumor progression and metabolic dysregulation, has emerged as a potential regulator of cachexia-related pathways. Here, we investigated the association between LIF in regulating GDF15 expression and its relationship with metabolic, inflammatory, and body composition alterations in gastric cancer. Transcriptomic profiling of paired neoplastic and non-neoplastic gastric mucosa from 61 gastric cancer patients revealed a significant upregulation of both LIF and GDF15 in tumor tissue, with a strong positive correlation between their expression levels. High GDF15 expression was associated with reduced overall survival, a finding validated in independent TCGA-STAD and ACRG cohorts. Intratumoral bile acid profiling uncovered a marked enrichment of primary bile acids and a depletion of secondary bile acids, resulting in reduced levels of bile acids with endogenous LIF receptor (LIFR) antagonist activity; elevated primary, LIFR non-antagonist bile acids were associated with worse survival outcomes. Clinically, increased LIF and GDF15 expression correlated with weight loss, heightened inflammatory burden, reduced serum protein and albumin levels, and impaired body composition in a sub-cohort of 19 patients. Notably, LIF expression showed a significant inverse association with both lumbar skeletal muscle index (L3SMI) and subcutaneous adipose tissue index (SATI). Mechanistically, experimental models demonstrated that LIF enhances proliferative activity in gastric cancer spheroids and exerts paracrine effects that impair myogenic differentiation and suppress hepatic metabolic gene expression. Collectively, these findings identify the LIF/GDF15 axis as a central driver of cancer-associated cachexia in gastric cancer and highlight LIF signaling as a potential therapeutic target.

Keywords:  bile acids; cancer cachexia; gastric cancer; growth differentiation factor 15 (GDF15); leukemia inhibitory factor (LIF); metabolic remodeling; skeletal muscle wasting

DOI:  https://doi.org/10.3390/cells15040355
bioRxiv. 2026 Feb 20. pii: 2026.02.19.706635. [Epub ahead of print]

Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.

Tulika Malik, Sam Jones, Olivia Ma, Sahana Mohan, R Michael Burger, Daniel T Babcock.

Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.

DOI: https://doi.org/10.64898/2026.02.19.706635
medRxiv. 2026 Feb 17. pii: 2026.02.15.26346348. [Epub ahead of print]

A network-based atlas of human skeletal muscle aging.

Tanner Stokes, Changhyun Lim, Muhammad Ali, Jonathan C Mcleod, Jack Gisby, Katia Mariniello, Hannah Crossland, Jalil-Ahmad Sharif, Colleen Deane, Thomas C Moseley, Nasim M Ismail, M E Lixandrao, C H Volmar, Peter J McCormick, Robert J Brogan, James Whiteford, H Roschel, Stuart M Phillips, Iain J Gallagher, Gregory Slabaugh, Bethan E Phillips, William E Kraus, Philip J Atherton, J Paul Chapple, James A Timmons.

Skeletal muscle metabolic and physical capacities are influenced by both genetics and load status and decline with age. Recent advances in sequencing have detailed cell types at unprecedented detail; yet these approaches do not scale to adequately model human muscle physiological heterogeneity. We produced a powerful resource for ageing studies, including consistent deep transcriptomic profiles of 1,675 human muscle biopsies (∼28,000 genes per profile) and multiple single-cell spatial transcriptomic technologies. We present several novel models of tissue ageing. Five Quantitative network models (QNMs), built using >40 trillion calculations and 930 human muscle transcriptomes, modelled aging and the influence of load status. Additional differential expression (DE) signatures for atrophy, hypertrophy and cardio-respiratory adaptation were integrated with single-cell RNAseq and cell-specific bulk profiles to reveal cell-enriched modules and the topology of human skeletal aging. Rapamycin transcriptomes from cultured muscle and endothelial cells, along with in vivo signatures for insulin resistance and sex, were integrated into these analyses. We show that >3,000 genes are DE with muscle age (equally up and down); that a novel pre-frailty signature in elderly subjects has a remarkably strong overlap with the response of healthy muscle during experimental atrophy and that the hypertrophy signature in elderly muscle, but not young muscle, opposes the age-regulated transcriptome. We report that non-responders for hypertrophy or gains in cardio-respiratory capacity have highly distinct genome-level response to exercise. QNM revealed cell-specific processes in endothelial cells and fibroblasts, including novel interactions between insulin sensitivity, age and senescence. From two hundred and eighty-six hub genes consistent in both young and old muscle network models, 27% had known roles in muscle biology, while of the top 50 hub genes (45% protein coding), 80% were newly linked to human muscle biology, including ARHGAP4, CEP131 and IFITM10 and many short- and long-noncoding RNAs. Many genes demonstrated extreme changes in topology in old muscle, such as the neddylation and aging linked gene, DCUN1D5. GeoMX-based spatial muscle fibre-type profiling (57 regions), along with Xenium (8 regions) and Merscope (54 regions) single-cell spatial technologies located key aging, frailty and load-responsive genes to individual cell types and provided novel insight into the location of autocrine/paracrine secreted factors such as GDNF, while IL6 was located to rare endothelial cells. A machine-learning model ranked the factors most associated with the topological changes with age. This prioritised network features over DE signatures, highlighting positive correlating edges to down-regulated genes during atrophy, genes up-regulated by Rapamycin and both positive and negative correlating insulin sensitivity features, along with gene hub status, best explained muscle ageing. Genome level modelling produced an independently validated transcriptomic 'age clock' and found it to be invariant to muscle load status in people >50y, while we revealed novel interactions between gene length and age. Release of an unprecedented level of consistently aligned genomic data, along with QNMs with >7,000 searchable modules, provides a powerful resource for the aging research communities.

DOI: https://doi.org/10.64898/2026.02.15.26346348
J Transl Med. 2026 Feb 25.

Role of mitochondrial dysfunction in muscle wasting in cancer cachexia: a narrative review.

Xiaoyu Su, Sutong Wang, Yiwei Qu, Yong Wang, Zhihan Tian, Xingliang Chao, Ziyuan Li, Dufang Ma.



Keywords:  Cachexia; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Muscle wasting

DOI:  https://doi.org/10.1186/s12967-026-07906-8
bioRxiv. 2026 Feb 13. pii: 2026.02.11.705439. [Epub ahead of print]

TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo.

Alicia Dubinski, Ala Ferdi, Mariam Choughari, Holly Spence, Arpita Adhikary, Carolane Fauchon, Melissa Touati, Myriam Gagné, Martha Liu, Sarah Peyrard, Jenna Gregory, Christine Vande Velde.

Nuclear depletion and cytoplasmic aggregation of TDP-43 are pathological hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease, and the recently defined limbic-predominant age-related TDP-43 encephalopathy (LATE). Chronic activation of the integrated stress response (ISR) and persistence of stress granules, phase-separated assemblies proposed to function as a protective mechanism, have been hypothesized to initiate the formation of pathological TDP-43 inclusions observed in post-mortem neurons. However, recent clinical trials targeting the ISR and stress granule dissolution failed to demonstrate clinical benefit despite robust target engagement, calling this model into question. Here, we employ a recurrent hyperthermia paradigm to directly examine the relationship between stress granules and TDP-43 pathology in vivo . We find that RNA-binding proteins classically associated with stress granules persist as phase-separated cytoplasmic structures in spinal motor neurons of both non-transgenic and mutant TDP-43 mice. Importantly, these structures are reversible and spatially distinct from TDP-43 puncta. Moreover, in a mutant TDP-43 mouse model with an impaired acute stress granule response, stress exposure induces TDP-43 nuclear export and cytoplasmic accumulation. Recurrent stress in these mice leads to a selective loss of spinal α-motor neurons. Together, our findings demonstrate that TDP-43 nuclear clearance and cytoplasmic demixing occur independently of stress granules in vivo , challenging prevailing models of TDP-43 pathogenesis and highlighting important implications for therapeutic strategies targeting the ISR.

DOI: https://doi.org/10.64898/2026.02.11.705439
Cancers (Basel). 2026 Feb 17. pii: 655. [Epub ahead of print]18(4):

Circulating Inflammatory and Mitochondrial Biomarkers Associated with Cachexia in Advanced Non-Small Cell Lung Cancer.

Kamya Sankar, Elham Kazemian, Nicole Lorona, Carlos D Cruz-Hernández, Alex K Bryant, Mitra Mastali, Akil A Merchant, Jennifer Van Eyk, Karen L Reckamp, Puneeth Iyengar, Neil A Bhowmick, Jane C Figueiredo.

  Background: Cancer-associated cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and/or adipose tissue loss and affects approximately 40% of patients with non-small cell lung cancer (NSCLC). However, reliable circulating biomarkers for early detection and risk stratification remain undefined. Based on prior observations linking elevated circulating mitochondrial DNA (mtDNA) to cachexia, we hypothesized that mtDNA and inflammatory protein levels in plasma could predict cachexia onset and trajectories. Methods: We evaluated 27 patients with stage IV NSCLC enrolled in the SeroNet-CORALE cohort with plasma samples collected between 2020 and 2023. Forty biomarkers were quantified at two timepoints (T1 and T2) using a multiplexed MesoScale Discovery platform. Associations between log2-transformed biomarker levels and cachexia status were assessed using Firth's penalized logistic regression. Results: Among 27 patients (65% female; mean age 65 ± 10 years; 89% adenocarcinoma histology), cachectic patients exhibited lower body mass index at both time points (T1: 21.0 ± 2.0 vs. 27.0 ± 7.0; T2: 21.8 ± 4.9 vs. 25.2 ± 4.9). At T1, cachexia was strongly associated with elevated GDF15 (OR 4.29; 95% CI 1.04-29.74; p = 0.044) and IL-15 (OR 43.83; 95% CI 2.39->999; p = 0.007), whereas IL-4 had a protective association (OR 0.09; 95% CI 0.00-0.66; p = 0.013). At T2, cachexia was associated with higher mtDNA levels (OR 2.13; 95% CI 1.07-7.69; p = 0.022) and lower levels of IL-15, IL12/IL23p40, and MDC. Conclusions: Distinct inflammatory and mitochondrial biomarkers tracked cachexia evolution in advanced NSCLC, with early GDF-15/IL-15 elevations and later increases in circulating mtDNA. Larger longitudinal studies are warranted to validate these findings and define their clinical relevance.

Keywords:  biomarkers; cachexia; mitochondrial DNA; non-small cell lung cancer

DOI:  https://doi.org/10.3390/cancers18040655
Adv Sci (Weinh). 2026 Feb 25. e22726

Repeated Disuse Atrophy Imprints a Molecular Memory in Skeletal Muscle: Transcriptional Resilience in Young Adults and Susceptibility in Aged Muscle.

Daniel C Turner, Truls Raastad, Max Ullrich, Stian F Christiansen, Hazel Sutherland, James Boot, Eva Wozniak, Charles Mein, Emilie Dalbram, Jonas T Treebak, Daniel J Owens, David C Hughes, Sue C Bodine, Jonathan C Jarvis, Adam P Sharples.

  Disuse-induced muscle atrophy commonly occurs following illness, injury, or falls and becomes increasingly frequent with ageing. Whether skeletal muscle retains a "memory" of repeated disuse remains unknown. We investigated repeated lower-limb immobilization in young adults and a refined aged rat model, integrating physiological, multi-omic, immunohistochemical, biochemical, and primary human muscle stem cell (MuSC) analyses. To enable robust age comparisons, we integrated previously published young rat data with newly generated aged rat data. In young human muscle, repeated disuse elicited attenuated transcriptional perturbations in oxidative and mitochondrial pathways, suggestive of a protective molecular memory, despite similar atrophy to initial disuse. In contrast, aged muscle exhibited a detrimental memory, characterized by greater atrophy, exaggerated suppression of aerobic metabolism genes despite recovery after initial disuse, NAD+ and mitochondrial DNA depletion, and activation of proteasomal, extracellular-matrix, and DNA-damage pathways. Whereas young rats recovered muscle mass after initial disuse, aged rats failed to do so. Across species, repeated disuse induced DNA hypermethylation and downregulation of aerobic metabolism and mitochondrial gene networks. NR4A1 and NR4A3 were among the strongest disuse-suppressed genes; NR4A1 acquired recovery-phase hypermethylation that maintained its transcriptional repression, while NR4A3 was the most downregulated gene after initial atrophy and remained persistently suppressed into recovery. Acetylcholine receptor subunit genes (CHRNA1, CHRND) were epigenetically primed, demonstrating hypomethylation and strong upregulation after disuse, and further amplification after repeated atrophy, while CHRNG was selectively induced after repeated atrophy only. NMRK2, an NAD+ biosynthesis gene, was the most downregulated gene across both atrophy periods, and supplementation with its substrate, nicotinamide riboside (NR), improved myotube size in MuSCs derived post-atrophy. Overall, repeated disuse atrophy imprints a molecular memory in skeletal muscle shaping transcriptional resilience in young adults and exaggerated susceptibility in aged muscle.

Keywords:  AChR (CHRNA1, CHRND, CHRNG); DNA methylation; NAD+ metabolism; NMRK2; NR4A1; NR4A3 ; aerobic metabolism; aging; disuse atrophy; mtDNA; muscle memory; muscle stem cells; nicotinamide riboside; skeletal muscle; transcriptome

DOI:  https://doi.org/10.1002/advs.202522726
Mol Ther. 2026 Feb 23. pii: S1525-0016(26)00119-X. [Epub ahead of print]

AUF1 therapy blocks atrophy, promotes regeneration, re-innervation and strength for severe muscle injury.

Dounia Abbadi, Olga Katsara, Riley McConnell, Beth Walters, Karol Granados Blanco, Alberto Canfrán-Duque, Sophie Dornbaum, John J Andrews, Robert J Schneider.

There are currently no approved therapeutic interventions to promote skeletal muscle regeneration following a severe muscle injury, among the most common of debilitating injuries. We developed a novel therapeutic approach, gene or mRNA delivery encoding RNA binding protein AUF1, which orchestrates the end-to-end process of myogenesis, for severe muscle injury. AUF1 supplementation significantly prevents muscle atrophy after severe injury while promoting rapid and complete functional muscle regeneration, and reinnervation by coordinating stability and translation of key myogenic mRNAs. In preclinical mouse models of skeletal muscle injury, prophylactic systemic administration of muscle-specific AAV8 AUF1 or intramuscular administration of AAV8 AUF1, as well as LNP AUF1 mRNA 24 hours after injury, were all highly effective in blocking muscle atrophy and accelerating muscle regeneration. Histologic, ultrastructural and biochemical analyses show that AUF1 supplementation strongly reduces muscle atrophy, and accelerates muscle regeneration and re-innervation. Animals receiving AUF1 therapy following muscle injury preserve near-normal muscle strength and function, whereas control animals demonstrate a significant, persistent decline in strength. These findings identify AUF1 therapy as a potential new approach to accelerate muscle recovery and repair, and reduce atrophy following injury.

DOI: https://doi.org/10.1016/j.ymthe.2026.02.033
Biomedicines. 2026 Feb 06. pii: 383. [Epub ahead of print]14(2):

The Muscle Function Deficit Concept and Inflammaging.

Giada Mariano, Matteo Candeloro, Raffaello Pellegrino, Roberto Paganelli, Angelo Di Iorio.

  Aging-related muscle dysfunction has been conceptualized through the model of sarcopenia, but it embraces several other characteristics, e.g., dynapenia, myosteatosis, and powerpenia. Our perspective reframes muscle aging from a different point of view, the Skeletal Muscle Function Deficit (SMFD), a unifying approach that integrates muscle quality and mass into a single functional definition. An SMFD score has been adopted in the InCHIANTI study against many geriatric outcomes, such as risk of disability, physical performance, hospitalizations and falls, and incidence of major diseases, highlighting its potential value as a primary indicator of muscle failure and/or of healthy aging. At the core of SMFD lies inflammaging, the chronic, low-grade, age-related inflammation, linking functional outcomes to muscular and neural aging. Inflammatory mediators alter the anabolic/catabolic balance, accelerate myosteatosis, impair neuromuscular junction, and influence denervation. These findings support the idea of a common pathway that links neuro-muscular deficit and inflammation, which simultaneously targets cortical motor circuits, spinal motor neurons, peripheral nerves, and muscle fibers. The SMFD approach facilitates early detection, risk stratification, and possible intervention for muscle deterioration with aging.

Keywords:  inflammaging; sarcopenia; skeletal muscle function deficit

DOI:  https://doi.org/10.3390/biomedicines14020383
Science. 2026 Feb 26. 391(6788): eadw6273

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.

Ziyu Lu, Zehao Zhang, Zihan Xu, Abdulraouf Abdulraouf, Wei Zhou, Junyue Cao.

To investigate organism-wide cellular alterations and epigenomic dynamics during aging, we constructed a single-cell chromatin accessibility atlas spanning 21 mouse tissues across three age groups and both sexes. We found that around one-quarter of 536 organ-specific cell types and 1828 finer-grained subtypes exhibited considerable age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, indicating systemic signals that coordinate these changes. Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying these shifts. Moreover, ~40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.

DOI: https://doi.org/10.1126/science.adw6273
J Physiol. 2026 Feb 24.

Translational studies of chronic supplementation with a mitochondria-targeted antioxidant to improve physical function with ageing.

Kevin O Murray, Rachel A Gioscia-Ryan, Jaime N Justice, Jessica R Santos-Parker, Nina Z Bispham, David A Hutton, Sanna Darvish, Jill Miyamoto-Ditmon, Zachary S Clayton, Michel Chonchol, Douglas R Seals, Matthew J Rossman.

  Declines in physical function with advancing age increase the risk of functional limitations and chronic disease. Excess mitochondrial reactive oxygen species (mitoROS)-related oxidative stress is linked to physical dysfunction with ageing, but the effects of therapies targeting excess mitoROS on age-associated physical dysfunction are unclear. Here, we determined the efficacy of the mitochondria-targeted antioxidant MitoQ for improving multiple domains of physical function, first in old mice and then in high-functioning older adults in a randomized, placebo-controlled, cross-over design clinical trial. In old male C57BL6/N mice (N = 22-26; 27 months), we found that 4 weeks of treatment with MitoQ (250 µm in the drinking water) attenuated the age-related decline in grip strength, co-ordination, and endurance without effects in young mice (N = 18-20; 6 months). The effects of MitoQ in old mice were accompanied by lower levels of skeletal muscle mitochondria-specific superoxide production and markers of mitoROS-related oxidative stress (i.e. phosphorylated SHC adaptor protein 1, isoform p66) and inflammation (i.e. interleukin-6, tumour necrosis factor-alpha, interferon-gamma). In the clinical trial, we did not observe convincing effects of 6 weeks of MitoQ (20 mg day-1) treatment on physical function in healthy older adults (N = 18; aged 60-79 years). However, exploratory subgroup analyses suggest possible effects of MitoQ on peak leg extension power and grip strength in participants ≥70 years of age. Our findings provide preclinical, proof-of-concept evidence for targeting excess mitoROS with MitoQ to reverse physical dysfunction with ageing. Although the effects of MitoQ did not directly translate to high functioning older adults, our initial observations suggest MitoQ may have greater efficacy in older, more physically frail individuals. KEY POINTS: Excess mitochondrial reactive oxygen species (mitoROS)-related oxidative stress is linked to physical dysfunction with ageing, but the effects of therapies targeting excess mitoROS on age-associated physical dysfunction are unclear. In old mice, chronic supplementation with the mitochondria-targeted antioxidant MitoQ improves measures of physical function, which was accompanied by reductions in mitochondria-specific superoxide production in skeletal muscle. The effects of MitoQ in old mice did not directly translate to humans as there were no convincing effects on measures of motor function in a randomized, placebo-controlled, cross-over design clinical trial of 6 weeks of 20 mg day-1 MitoQ. However, in participants ≥70 years of age, we observed possible evidence of efficacy of MitoQ supplementation for improving select measures of strength. Future clinical trials with MitoQ and possibly other mitochondria-targeted antioxidant approaches for enhancing physical function with ageing should focus on older adults of more advanced age or more frail clinical populations.

Keywords:  MitoQ; inflammation; motor function; older adults; postmenopausal women; reactive oxygen species; skeletal muscle; superoxide

DOI:  https://doi.org/10.1113/JP289428
Curr Issues Mol Biol. 2026 Jan 27. pii: 135. [Epub ahead of print]48(2):

The Effects of ACTH and Dexamethasone on the Transcriptomic Profile of the Rat Adrenal Gland: An In Vivo Study.

Emilia Cicha, Małgorzata Blatkiewicz, Karol Jopek, Marta Szyszka, Piotr W Malendowicz, Anna Olechnowicz, Ludwik K Malendowicz, Marcin Rucinski.

  The hypothalamic-pituitary-adrenal (HPA) axis plays a pivotal role in regulating stress responses through ACTH-stimulated glucocorticoid production. The transcriptional programmes underlying temporal adaptation to prolonged ACTH exposure and glucocorticoid feedback remain incompletely characterized. Adult male Wistar rats were subjected to acute ACTH stimulation (single injection, 1 h) to elicit an immediate transcriptional response, prolonged ACTH exposure (three injections over 36 h) as a repeated exposure, or Dexamethasone treatment (three injections over 36 h). Plasma corticosterone levels were subsequently measured using an enzyme-linked immunosorbent assay (ELISA). The adrenal transcriptome profiling was performed using Affymetrix arrays. Differentially expressed genes (DEGs; |fold change| ≥ 1.8, adjusted p < 0.05) were analyzed using limma, followed by pathway and network analyses. Acute ACTH exposure resulted in the induction of 569 DEGs (357 upregulated), including immediate-early genes (Nr4a family, AP-1 factors), cAMP-PKA-CREB signalling components, and heat shock proteins. Prolonged ACTH resulted in 98 DEGs (predominantly downregulated), including the suppression of mitochondrial genes and upregulation of Polycomb repressive complex 2 components, suggesting epigenetic transcriptional attenuation. Dexamethasone treatment yielded 75 DEGs with selective suppression of SREBP-mediated cholesterol biosynthesis and uptake pathways. Twelve genes were downregulated by both prolonged ACTH and Dexamethasone, including sterol metabolism and interferon-stimulated genes. Acute and prolonged ACTH exposure engage distinct transcriptional programmes. Acute stimulation activates immediate-early genes and stress responses, while prolonged exposure suppresses mitochondrial gene expression through transcriptional dampening mechanisms. Dexamethasone is associated with the inhibition of cholesterol metabolism via SREBP pathway suppression. These findings illuminate HPA axis adaptation and glucocorticoid-induced adrenal suppression.

Keywords:  ACTH; Nr4a; SREBP; adrenal cortex; glucocorticoids; immediate-early genes; microarray; mitochondria; steroidogenesis; transcriptome

DOI:  https://doi.org/10.3390/cimb48020135
Front Cell Neurosci. 2026 ;20 1731669

C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.

James A K Lee, Chloe Moutin, Sarah Granger, Katie Roome, Allan Shaw, Scott P Allen, Laura Ferraiuolo, Pamela J Shaw, Heather Mortiboys.

   Introduction: ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.
Results: iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.
Conclusion: Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.

Keywords:  ALS (Amyotrophic lateral sclerosis); ULK1; autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.3389/fncel.2026.1731669
Neurobiol Aging. 2026 Feb 23. pii: S0197-4580(26)00026-6. [Epub ahead of print]162 57-65

Nerve, muscle and adiposity: Associations with gait speed across adulthood in the Baltimore Longitudinal Study of Aging.

Marcel Bahia Lanza, Matheus B Guerrero, Vicki L Gray, Eleanor M Simonsick.

  Walking is fundamental to human mobility, and slowing gait speed is a widely recognized indicator of aging-related mobility decline. Although mobility decline in older adults has been associated with aging-related neural and morphological changes in muscle, the specific neural and morphological correlates of gait speed remain incompletely characterized. Thus, our primary aim was to quantify how peripheral nerve function, muscle cross-sectional area (MCSA) and intramuscular fat (IMAT) are related to gait speed across adulthood. We studied 898 participants from the Baltimore Longitudinal Study of Aging (BLSA), aged ≥ 20 years, with complete data on gait speed, body composition, MCSA, IMAT, and peripheral nerve function. Multivariable regression explained 29 % and 40 % of the variance in usual and rapid gait speed, respectively. Peripheral nerve measures (signal amplitude and conduction velocity) showed modest associations with both usual and rapid gait speed after mutual adjustment. In contrast, age, height, body roundness index (BRI), MCSA, and IMAT were independently associated with both gait speeds. Structural equation modelling identified MCSA and IMAT as the primary mediators of age-related gait decline, while nerve function played a smaller, task-specific role. Multi-group analysis revealed that these physiological mechanisms were stable across adulthood; however, the direct effect of age on rapid gait attenuated in the oldest-old, indicating that functional decline in this cohort is fully mediated by neuromuscular and morphological factors. Together, these findings indicate that peripheral nerve function contributes to gait speed across adulthood but plays a comparatively limited role relative to muscle morphology (MCSA and IMAT), which emerge as dominant physiological contributors to age-related mobility decline.

Keywords:  Gait speed; Intramuscular fat; Muscle size; Older adults; Peripheral nerve function; Structural equation modelling

DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.02.005
bioRxiv. 2026 Feb 13. pii: 2026.02.11.705446. [Epub ahead of print]

Myonuclear loss, rather than senescent myonuclei, associates with fiber type-specific atrophy in aging human skeletal muscle.

Carlos S Zepeda, Isabell Dobrzycki, Paige N Acklie, Cory M Dungan, Ronald G Jones, Kevin A Murach, Christopher W Sundberg.

Age-related reductions in whole-muscle function are attributed, in part, to pronounced atrophy of muscle fibers expressing the fast myosin heavy chain (MyHC) II isoforms. Senescence, a state of irreversible cell cycle arrest that can be characterized by DNA damage (γH2AX) and chromatin remodeling (loss of nuclear HMGB1), may contribute to skeletal muscle aging. Muscle nuclei (myonuclei) maintain fiber size and function and could exhibit senescence-associated features; however, the prevalence of senescent myonuclei and whether they contribute to fast fiber atrophy in older adults remains unknown. Vastus lateralis biopsies from 20 young (19-34yr; 10 females) and 20 older (65-84yr; 10 females) adults were analyzed via immunohistochemistry for myonuclei positive for γH2AX (γH2AX+) and negative for HMGB1 (HMGB1-). MyHC II cross-sectional area (CSA) was ~70% larger in young compared with old, whereas MyHC I CSA did not differ with age. The relative abundance of γH2AX+/HMGB1- myonuclei did not differ with age and was not associated with CSA in either fiber type. Single-nucleus RNA-sequencing corroborated no age-related difference in the prevalence of myonuclei with senescence-associated features. Myonuclear content of MyHC II fibers was ~30% higher in young compared with old and was closely associated with CSA in both fiber types. Size-cluster analysis revealed a pronounced age-related leftward shift in MyHC II CSA that paralleled the reductions in myonuclear number, consistent with myonuclear loss. These data suggest that age-related fast fiber atrophy is not attributed to an increased prevalence of senescent myonuclei but instead occurs concomitantly with fiber type-specific myonuclear loss across the lifespan.

DOI: https://doi.org/10.64898/2026.02.11.705446
Aging Cell. 2026 Mar;25(3): e70403

Select Small Non-Coding RNAs Are Determinants of Survival in Older Adults.

Virginia Byers Kraus, Sisi Ma, Syeda Iffat Naz, Xin Zhang, Christopher G Vann, Melissa C Orenduff, William E Kraus, Steven Shen, Janet L Huebner, Ching-Heng Chou, Erich Kummerfeld, Harvey Jay Cohen, Constantin F Aliferis.

  To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs-687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs)-in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the Duke-EPESE study. Our predictive model incorporating smRNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated AUCs of 0.92 for 2-year survival in Discovery and 0.87 in external Validation. Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.

Keywords:  HDL lipoproteins; RNA; aging; causality; epigenetic processes; microRNAs; piwi‐interacting RNA; survival

DOI:  https://doi.org/10.1111/acel.70403
bioRxiv. 2026 Feb 11. pii: 2026.02.09.704867. [Epub ahead of print]

Nerve Injury-Induced Protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.

Jin Zhang, Miranda Bustamante, Yang Shi, Ken-Ichi Nakajima, Xinbin Chen.

Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for the lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of Ninj2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.

DOI: https://doi.org/10.64898/2026.02.09.704867