bims-musmir 2026-06-14 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–06–14
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.
Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.
The cGAS-STING pathway contributes to cisplatin-induced skeletal muscle atrophy through altered proteostasis and myogenic signaling.
Fasting requires Peroxiredoxin 2 and Peroxiredoxin 6 to coordinate redox dependent mitochondrial and lipid remodelling in Caenorhabditis elegans.
LaminA/C-dependent cellular senescence signaling promotes skeletal muscle atrophy and abnormalities in Parkinson's disease.
microRNA-1: A Master Regulator of Metabolism Governing Skeletal Muscle Hypertrophy.
Expression of four mitochondrial tRNAs from only two loci.
Shenling Baizhu Decoction Improves Chemotherapy-Induced Sarcopenia by Regulating the NLRP3 Inflammasome and Muscle Metabolism.
Mitochondria-ER contacts function as an iron supply hub.
18F FDG-PET correlates of motor neuron disease motor variants.
Endurance exercise elicits temporal and sexual dimorphic multi-omics remodeling of liver metabolism revealed by MoTrPAC.
VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.
Long-term inhibition of lysosomal glucocerebrosidase activity promotes GPX4 stability and inhibits ferroptosis in dopaminergic neurons.
A protective role for APP in nuclear waste clearance via lysosomal exocytosis.
Flunarizine changes microRNA expression in cell cultures and in a mouse model of spinal muscular atrophy.

Front Med (Lausanne). 2026 ;13 1838178

MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.

Nicholas A Jamnick, Patrick D Livingston, Caleb J Gammon, Natalia M Weinzierl, Leah J Novinger, Andrea Bonetto.

   Background: Cancer cachexia is a multifactorial metabolic syndrome marked by progressive skeletal muscle loss, reduced function, and increased mortality. Mitochondrial dysfunction is a key driver of this phenotype. MOTS-c, a mitochondrial-derived peptide that regulates metabolic homeostasis and mimics exercise signaling, may counteract cachexia, but its role remains largely unexplored, and human studies using MOTS-c in subjects with cancer cachexia are needed.
Methods: Differentiated myotubes were treated with MOTS-c (50 μM) to assess intracellular signaling. In vivo, male mice were inoculated with Colon-26 (C26) carcinoma cells and treated daily with MOTS-c (15 mg/kg/2x Day, i.p.) or vehicle. Body weight was monitored daily. At euthanasia, organ and skeletal muscle masses were measured. Molecular analyses focused on FOXO signaling, atrogene expression (MuRF1, Atrogin-1), and mitochondrial biogenesis markers, including PGC-1α.
Results: In vitro, MOTS-c increased PGC-1α mRNA (+84.6%) and AMPK phosphorylation (+103.1%). C26 tumor-bearing mice exhibited significant systemic wasting (~9% body weight loss). Although MOTS-c did not prevent total body weight or fat loss, it significantly preserved skeletal muscle mass, rescuing quadriceps weight (+12% vs. C26 vehicle; p < 0.05) and trending toward protection of gastrocnemius mass and EDL function. Cachexia-induced upregulation of Atrogin-1 (+8.6-fold) and MuRF1 (+16-fold) was attenuated by MOTS-c, accompanied by increased inhibitory pFOXO1 (+80%), reduced pFOXO3a (-39%), and partial restoration of PGC-1α protein (+143%).
Conclusion: Our findings demonstrate that MOTS-c partially protects against skeletal muscle loss in C26 cachexia by modulating FOXO-driven catabolic signaling and promoting mitochondrial biogenesis, supporting its therapeutic potential in cancer cachexia.

Keywords:  MOTS-c; cachexia; colorectal cancer; muscle; protein homeostasis

DOI:  https://doi.org/10.3389/fmed.2026.1838178
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00114-5. [Epub ahead of print]403 85-121

Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.

Riccardo Ballarò, Fabio Penna, Marc Beltrà.

  Cancer cachexia is a multifactorial syndrome characterized by body weight loss, muscle wasting, and systemic metabolic alterations, significantly contributing to patient morbidity and mortality. A key feature of cachexia is the excessive degradation of muscle proteins and mitochondria, largely mediated by autophagy. Although hyperactivation of autophagy has been widely recognized as a hallmark of cancer cachexia, its precise role in exacerbating muscle atrophy through enhanced proteolysis and mitochondrial disposal remains a subject of ongoing debate. This review provides a comprehensive overview of previous milestones and recent advancements in understanding autophagy's role in cancer cachexia, with particular focus on its impact on skeletal muscle and liver, as well as its contribution to tumor metabolic flexibility. Additionally, the review explores emerging therapeutic strategies aimed at modulating autophagy, including exercise, exercise mimetics, and novel molecules to selectively target specific branches of autophagy. By synthesizing current evidence, this review highlights the need for further research into the mechanisms underlying autophagy dysregulation in cancer cachexia and the potential for autophagy-based interventions to improve patient outcomes.

Keywords:  Autophagy; Cancer cachexia; Diet therapy; Exercise; Liver metabolism; Mitophagy; Muscle wasting; Tumor metabolism

DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.008
Cell Commun Signal. 2026 Jun 12.

The cGAS-STING pathway contributes to cisplatin-induced skeletal muscle atrophy through altered proteostasis and myogenic signaling.

Xiaoguang Liu, Miaomiao Xu, Huan Wang, Haozhe Wang, Hao Wang, Wenjun Fang, Mengqian Li, Jiongxing Huang, Feipeng Chen, Huiguo Wang, Yang Yu, Lin Zhu.

   BACKGROUND: Cisplatin chemotherapy is widely used for cancer treatment but frequently induces skeletal muscle atrophy, which compromises physical function and patient outcomes. The molecular mechanisms underlying this process remain incompletely understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, classically involved in innate immune responses, has recently been implicated in cellular stress and tissue dysfunction. Whether cGAS-STING signaling contributes to cisplatin-induced skeletal muscle atrophy remains unclear.
METHODS: We employed both pharmacological and genetic approaches. Wild-type (WT) mice received a single intraperitoneal injection of the STING agonist DMXAA prior to cisplatin administration. Genetic models included global cGAS and STING knockout mice, as well as skeletal muscle-specific cGAS knockout mice. Cisplatin was administered intraperitoneally (3 mg/kg/day) for four consecutive days. Body weight, skeletal muscle mass, myofiber cross-sectional area (CSA), and fiber diameter were assessed. Molecular and transcriptional analyses were performed using Western blotting, quantitative polymerase chain reaction, and RNA sequencing.
RESULTS: Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass. Skeletal muscle-specific cGAS deficiency preserved muscle weight and myofiber diameter following cisplatin exposure. Although CSA was also assessed, no significant difference was observed between groups. Transcriptomic analysis identified 696 differentially expressed genes upon cGAS deletion, with enrichment in pathways related to inflammatory signaling, proteasome function, and autophagy. Further analyses in skeletal muscle-specific cGAS-deficient mice showed reduced expression of muscle atrophy-associated genes (FBXO32 and Murf1), together with preservation of key myogenic regulators after cisplatin treatment. Consistently, NF-κB signaling and interferon-stimulated gene expression were diminished, accompanied by altered Beclin1 responses and partial attenuation of selected autophagy-related genes.
CONCLUSIONS: These findings support a role for cGAS-STING signaling in cisplatin-induced skeletal muscle atrophy, associated with enhanced innate immune and inflammatory signaling, proteolytic and autophagy-related alterations, and impaired myogenic regulation. Targeting the cGAS-STING pathway may represent a potential therapeutic strategy to mitigate chemotherapy-associated skeletal muscle atrophy.

Keywords:  CGAS–STING pathway; Chemotherapy-induced skeletal muscle atrophy; Cisplatin toxicity; Skeletal muscle wasting; Therapeutic target

DOI:  https://doi.org/10.1186/s12964-026-02989-8
Redox Biol. 2026 May 22. pii: S2213-2317(26)00229-6. [Epub ahead of print]95 104231

Fasting requires Peroxiredoxin 2 and Peroxiredoxin 6 to coordinate redox dependent mitochondrial and lipid remodelling in Caenorhabditis elegans.

Penglin Li, Yating Zheng, Jose C Casas-Martinez, Qin Xia, Antonio Miranda-Vizuete, Katarzyna Goljanek-Whysall, Brian McDonagh.

  Fasting induces conserved metabolic and redox adaptations that promote stress resistance and longevity. However, the molecular mechanisms linking transient redox changes and altered metabolism to downstream signalling events remain incompletely understood. Using Caenorhabditis elegans, the roles of peroxiredoxins in coordinating redox-dependent responses to fasting and refeeding were determined. A 4-hr fasting protocol over 5 days extended lifespan, improved late-life physiological activity, reduced age-related lipofuscin and lipid accumulation. The fasting protocol generated a transient increase in mitochondrial ROS, promoted mitochondrial turnover, and attenuated age-related mitochondrial fragmentation. These adaptive responses required the activation and nuclear localisation of the stress-responsive transcription factors DAF-16/FOXO and SKN-1/Nrf2. However, these adaptive responses were abolished in prdx-2 and prdx-6 mutant strains, which exhibited persistent redox imbalance, mitochondrial fragmentation, altered stress resistance, and disrupted DAF-16 and SKN-1 signalling. Mechanistically, loss of 2-Cys PRDX-2 impaired activation of the p38 MAPK PMK-1 pathway, resulting in defective SKN-1 activation. In contrast, loss of 1-Cys PRDX-6 disrupted lipid metabolic signalling, preventing induction of NHR-80 and downstream fatty acid desaturases required for metabolic adaptations. Despite distinct initial signalling pathways, both peroxiredoxins converged on the regulation of DAF-16 and SKN-1. Together, these findings identify PRDX-2 and PRDX-6 as redox sensors that translate a fasting-induced transient ROS signature into mitochondrial and lipid remodelling pathways to promote healthy ageing.

Keywords:  Ageing; Fasting; Lipid remodelling; Mitochondrial dynamics; Oleic acid; Peroxiredoxin

DOI:  https://doi.org/10.1016/j.redox.2026.104231
Cell Death Dis. 2026 Jun 06.

LaminA/C-dependent cellular senescence signaling promotes skeletal muscle atrophy and abnormalities in Parkinson's disease.

Jaydeep Sharma, Somnath Mondal, Krishna Singh Bisht, Ankit Biswas, Lakshmikanthan Panneerselvam, Tushar Kanti Maiti, Sam J Mathew.

Parkinson's disease (PD) is a neurodegenerative disease affecting the central nervous system with effects on the skeletal muscle that entails detailed characterization. Several PD-associated motor symptoms, such as rigidity, movement delays and postural instability, involve the skeletal muscle. We used the human α-syn A53T mutant mouse model to characterize the PD-associated skeletal muscle abnormalities. These mice exhibit reduced muscle weight, myofiber size and grip strength at PD onset. Gain of slow muscle fibers at the expense of fast fibers, muscle stem cell number alterations, elevated fibrosis and neuromuscular junction degeneration were observed in these mice. Oxidative stress and DNA damage-associated pathways led to reduced levels of the nuclear membrane protein LaminA/C, causing accelerated cellular senescence in the A53T muscle. We identify a molecular pathway of senescence-associated secretory phenotype activating FoxO signaling, resulting in skeletal muscle loss in the A53T mice. Thus, increased oxidative stress and accumulated cellular senescence could underlie the PD-associated musculoskeletal defects, with potential therapeutic significance.

DOI: https://doi.org/10.1038/s41419-026-08962-0
Exerc Sport Sci Rev. 2026 Jul 01. 54(3): 127-133

microRNA-1: A Master Regulator of Metabolism Governing Skeletal Muscle Hypertrophy.

Jainil Daredia, Benjamin I Burke, John J McCarthy, Ahmed Ismaeel.

  Downregulation of microRNA-1 (miR-1), the most abundant muscle-enriched microRNA, represents a conserved hallmark of skeletal muscle hypertrophy across species. We propose that mechanical overload-induced reduction in miR-1 expression drives metabolic reprogramming critical for hypertrophic adaptation. This review explores emerging evidence establishing miR-1 as a master regulator of metabolism that governs skeletal muscle growth.

Keywords:  Warburg effect; aerobic glycolysis; extracellular vesicles; mechanical overload; metabolic reprogramming; pyruvate metabolism; resistance exercise training

DOI:  https://doi.org/10.1249/JES.0000000000000384
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2534946123

Expression of four mitochondrial tRNAs from only two loci.

Jessica M Warren, Kasavajhala V S K Prasad, Anistynn M Mendez, Stephanie Temnyk, John P McCutcheon.

  Transfer RNAs (tRNAs) are among the few genes retained in animal mitochondrial genomes after more than a billion years of gene loss. These ancient bacterial vestiges are often structurally aberrant and less stable than their bacterial or cytosolic tRNA counterparts. In some lineages, mitochondrial tRNAs (mt-tRNAs) have become so truncated that the loss of one or both arms has expanded our understanding of what constitutes a functional tRNA. Here, we report another radical departure from canonical tRNA gene architecture: two overlapping tRNAs produced from opposite strands of the same locus. These "mirror" tRNA pairs eliminate the need to retain separate loci for all tRNA genes, as a single locus can produce tRNAs to decode two different amino acids. We show that these mirror tRNAs are aminoacylated and demonstrate their presence in mitoribosomes. Furthermore, mirror tRNAs display strand-specific patterns of nucleotide modification and RNA editing, reflecting specific posttranscriptional maturation that depends on transcriptional orientation. This demonstration of functional, bidirectional tRNA expression reveals an unexpected strategy by which mitochondrial genomes maintain a complete set of tRNAs in the face of unrelenting gene loss. The presence of mirror tRNAs has broad implications for the evolution of tRNA-interacting enzymes, mitochondrial biology, and even the origins of the protein synthesis machinery itself.

Keywords:  bidirectional transcription; mitochondrial genome evolution; mitochondrial tRNAs

DOI:  https://doi.org/10.1073/pnas.2534946123
Curr Med Chem. 2026 Jun 08.

Shenling Baizhu Decoction Improves Chemotherapy-Induced Sarcopenia by Regulating the NLRP3 Inflammasome and Muscle Metabolism.

Jin Huang, Heiying Jin, Chunxia Zhang, Xiaochun Zhang.

   OBJECTIVE: This study investigated the effects of Shenling Baizhu decoction (SLBZD) on chemotherapy-induced sarcopenia and its potential mechanisms.
METHODS: A mouse model of chemotherapy-induced sarcopenia was established and treated with SLBZD. The effects of SLBZD on body weight, food intake, muscle mass, muscle functional markers, muscle tissue architecture, and serum biochemical parameters in mice receiving chemotherapy were determined, and the potential mechanism was investigated.
RESULTS: The study indicated that SLBZD effectively alleviated chemotherapy-induced weight loss and decreased food intake, muscle atrophy, and functional loss in mice. It increased the CSA level, decreased the serum IFN-γ, IL-1β, and TNF-α levels, increased ATP content and IGF-1 protein expression in muscle tissue, and down-regulated MSTN expression. SLBZD down-regulated the mRNA expressions of NLRP3, p65, Caspase-1, and MuRF1 and up-regulated the expression of MyoD. The mechanism is that SLBZD activated PPARγ, inhibited NF-κB phosphorylation, and suppressed NLRP3 inflammasome activation. Transcriptome analysis revealed the regulation of immune-inflammatory pathways and metabolic pathways. Additionally, SLBZD promoted myotube formation and diameter, regulated MuRF1/MyoD, and inhibited NLRP3/NF-κB signaling, effects that could be reversed by a PPARγ inhibitor.
DISCUSSION: The findings suggest that SLBZD can prevent sarcopenia by activating PPARγ to inhibit NF-κB/NLRP3 and restore metabolic homeostasis, thereby making it a promising adjunctive therapeutic regimen.
CONCLUSION: This study identifies SLBZD as a promising therapeutic agent for chemotherapy- induced sarcopenia, whose functions may be attributed to PPARγ-mediated regulation of inflammatory and metabolic pathways.

Keywords:  NLRP3 inflammasome; PPARγ.; Sarcopenia; shenling baizhu decoction; transcriptomics

DOI:  https://doi.org/10.2174/0109298673459977260522071210
Nat Cell Biol. 2026 Jun 10.

Mitochondria-ER contacts function as an iron supply hub.

Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.

Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.

DOI: https://doi.org/10.1038/s41556-026-01974-0
Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 09. 1-5

18F FDG-PET correlates of motor neuron disease motor variants.

Boris Deleu, Patrick Dupont, Kato Bracaval, Fouke Ombelet, Frederik Hobin, Nikita Lamaire, Koen Van Laere, Philip Van Damme, Joke De Vocht.

  While 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease (MND) motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of MNDs, including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), and ALS. We retrospectively included 18 PMA, 25 PLS, and 43 matched non-hereditary ALS patients according to most recent diagnostic criteria. FDG-PET imaging revealed similar widespread hypometabolism in PMA, as in ALS, whereas PLS showed a more focal motor cortical pattern of hypometabolism. Despite clinical differences between MND subtypes, PMA and ALS showed similar FDG-PET metabolic patterns, whereas PLS exhibited a more restricted cortical signature in this retrospective study.

Keywords:  18F FDG PET; Nuclear imaging; amyotrophic lateral sclerosis; motor neuron disease; primary lateral sclerosis; progressive muscular atrophy

DOI:  https://doi.org/10.1080/21678421.2026.2682820
Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00494-8. [Epub ahead of print]45(6): 117416

Endurance exercise elicits temporal and sexual dimorphic multi-omics remodeling of liver metabolism revealed by MoTrPAC.

MoTrPAC study group

  The mechanisms by which exercise modulates liver metabolism are poorly understood. Leveraging data from molecular transducers of physical activity consortium (MoTrPAC), we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omics approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) protein complexes, while male livers showed an increased acetylation of OXPHOS, tricarboxylic acid cycle, and fatty acid oxidation enzymes. Mechanistic examination revealed that these sex-specific acetylation events are partially mediated by carnitine acetyltransferase. Exercise enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Eight weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

Keywords:  CP: metabolism; CrAT; bile acids; endurance exercise; lipids; liver; metabolism; mitochondria; omics

DOI:  https://doi.org/10.1016/j.celrep.2026.117416
Tissue Cell. 2026 Jun 10. pii: S0040-8166(26)00386-1. [Epub ahead of print]103 103692

VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.

Rabab S Hamad, Eman Hamza, Ebtehal M Abdel-Aal, Elsayed A Elmorsy, Hanan Eissa, Alshaimaa A Farrag, Ahmed Shata, Ghada M Nassar, Nesreen Elsayed Morsy, Ahmed A El-Mansy, Ahmed G Hamad, Eman R Abdellatif, Sameh Saber.

  Organelle contact sites are increasingly recognized as regulatory interfaces that coordinate lipid transfer, ion signaling, and metabolic adaptation. In neurons, communication among the endoplasmic reticulum (ER), lysosomes, and mitochondria is essential for cellular homeostasis. Recent studies have identified vacuolar protein sorting 13 homolog C (VPS13C), a lipid transport protein, as a key mediator of ER-lysosome tethering and as an important component of the response to lysosomal stress. Structural analyses show that VPS13 family proteins form elongated lipid transport channels that are proposed to facilitate phospholipid transfer between adjacent membranes. Following lysosomal damage, VPS13C is recruited to ER-lysosome contact interfaces, where it forms tethering bridges that may support membrane repair by enabling high-capacity lipid transfer from the ER to lysosomal membranes. Beyond membrane repair, these contact interfaces may also participate in broader organelle communication networks. ER-lysosome contacts can occur in proximity to ER-mitochondria junctions, potentially forming multi organelle signaling hubs that coordinate lipid redistribution, calcium signaling, and mitochondrial adaptation. These signals may influence downstream responses, including activation of TFEB and TFE3, which regulate lysosomal biogenesis and autophagy. Disruption of this contact site network has emerged as a potential contributor to Parkinson's disease. Loss of VPS13C function is associated with altered lysosomal homeostasis and intersects with pathogenic pathways involving α-synuclein aggregation, PINK1/Parkin-mediated mitophagy, and LRRK2 signaling. This review presents a framework in which ER-lysosome tethering is considered part of a staged cellular damage response linking membrane repair, metabolic coordination, and transcriptional adaptation.

Keywords:  ER-lysosome tethering; Lipid transfer; Lysosomal membrane repair; Organelle contact sites; Parkinson’s disease; VPS13C

DOI:  https://doi.org/10.1016/j.tice.2026.103692
Cell Death Dis. 2026 Jun 08.

Long-term inhibition of lysosomal glucocerebrosidase activity promotes GPX4 stability and inhibits ferroptosis in dopaminergic neurons.

Marie-Amandine Bonte, Flore Gouel, Aurélie Jonneaux, Karim Belarbi, David Devos, Jean-Christophe Devedjian.

An increasing number of studies indicate that ferroptosis, a lethal pathway initiated by excessive iron-dependent lipid peroxidation, and pivotal to the survival of dopaminergic neurons and the progression of Parkinson's disease (PD), may be regulated by the lysosomal pathway. Mutation and loss of function of the lysosomal enzyme, glucocerebrosidase, induce the accumulation of glycosphingolipids and alterations in lysosome activity, which have been associated with a higher risk of developing PD. Our present study showed that transient inhibition of glucocerebrosidase activity had a positive effect on lipid peroxidation and ferroptosis. In a dopaminergic cell line (LUHMES cells), it was shown that a 10-day inhibition of glucocerebrosidase activity using conduritol-beta-epoxide (CBE) specifically impeded susceptibility to RSL3-induced ferroptosis, but not to several other inducers of cell death. CBE impaired the lysosomal pathway, modified lipid membrane composition by reducing ether-linked phospholipids in phosphatidylethanolamines, and promoted an increase in glutathione peroxidase 4 (GPX4) protein levels. This phenomenon was transient and disappeared after 20 days of glucocerebrosidase inhibition, suggesting that the cells have the capacity to return to their basal homeostasis. Most of the current compounds acting on GPX4 promote its degradation, thus information on drugs leading to GPX4 stability is key in order to protect neurons against excessive lipid peroxidation occurring in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41419-026-08833-8
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2524190123

A protective role for APP in nuclear waste clearance via lysosomal exocytosis.

Godfried Dougnon, Takayoshi Otsuka, Yuka Nakamura, Akiko Sakai, Tomoyuki Yamanaka, Noriko Matsui, Asa Nakahara, Ai Ito, Atsushi Hatano, Masaki Matsumoto, Hironaka Igarashi, Akiyoshi Kakita, Masaki Ueno, Hideaki Matsui.

  Amyloid precursor protein (APP) is widely known for its role in Alzheimer's disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear waste material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.

Keywords:  amyloid precursor protein; cellular homeostasis; lysosomal exocytosis; neurodegeneration; nuclear waste clearance

DOI:  https://doi.org/10.1073/pnas.2524190123
Sci Rep. 2026 Jun 08.

Flunarizine changes microRNA expression in cell cultures and in a mouse model of spinal muscular atrophy.

Emeline Bon, Perrine Delers, Florent Dumont, Badih Salman, Delphine Sapaly, Franck Letourneur, Anne-Sophie Armand, Suzie Lefebvre.

  Spinal muscular atrophy (SMA) is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to reduced SMN protein levels and widespread disruption in RNA metabolism. Despite of disease-modifying therapies, which remarkably improve patient outcomes, the long-term effects remain unknown. Dysregulated small non-coding RNAs, including microRNAs, have been reported in SMA, but their contribution to the disease remains unclear. We previously showed that flunarizine could improve the phenotype of an SMA mouse model; however its mode of action is incomplete. Here, we showed that flunarizine modulates the expression of numerous microRNAs. Using small-RNA sequencing of a flunarizine-treated SMA patient fibroblast cell line, we identified several microRNAs, which are also dysregulated in the brains and/or spinal cords of SMA mouse models at early disease stages and corrected with flunarizine. Transfection of the miR-128-3p inhibitor interferes with the flunarizine-induced neurite outgrowth in the murine neuronal NSC34 cells. Among the mRNAs modulated by flunarizine, homeodomain interacting protein kinase 2 (Hipk2) transcripts were revealed as novel miR-128-3p targets using either the mimic or its inhibitor. Our findings suggest that an early microRNA accumulation in spinal cords of SMA models can contribute to molecular dysfunctions and may represent an initiating event in pathogenesis.

Keywords:  Flunarizine; HIPK2; Neurodegeneration,; Spinal muscular atrophy,; miR-128; microRNAs

DOI:  https://doi.org/10.1038/s41598-026-56607-1