bims-musmir 2026-10-25 papers

iScience. 2026 Nov 20. 29(11): 117764

Targeting host ferroptosis in cancer cachexia: Tumor-immune triggers, tissue wasting, and the therapeutic paradox.

Cancer cachexia is a systemic wasting syndrome driven by tumor burden, chronic inflammation, disrupted nutrient handling, and neuroendocrine stress. Supportive nutrition, exercise, and symptom management rarely restore lean mass, function, or treatment tolerance once wasting is established. Ferroptosis, iron-dependent cell death caused by phospholipid peroxidation, may connect inflammatory iron redistribution, lipid remodeling, mitochondrial stress, and impaired antioxidant defenses. This review critically evaluates ferroptosis in cachexia from a tumor-host pharmacology perspective, distinguishing causal evidence from associated oxidative signatures. We highlight two experimentally supported mechanisms: neutrophil-derived lipocalin-2 in lung cancer cachexia and tumor exosomal miR-203a-3p in pancreatic cancer-associated muscle wasting. We also examine the paradox that tumor ferroptosis induction may weaken host-tissue resistance and worsen muscle and adipose loss. We propose a "split-ferroptosis" strategy combining tumor sensitization with host-protective iron modulation, lipid peroxide scavenging, endogenous defense reinforcement, and biomarker-guided patient selection to expand the tumor-host therapeutic index.

Keywords: adipose tissue loss; cancer cachexia; ferroptosis; iron metabolism; lipid peroxidation; skeletal muscle wasting

DOI: https://doi.org/10.1016/j.isci.2026.117764

Mol Pain. 2026 Jan-Dec;22:22 17448069261499172

Skeletal muscle transcriptomic profile of older adults with high-impact musculoskeletal pain in the study of muscle, mobility and aging (SOMMA).

Javier A Tamargo, Yutao Zhang, Muhammad Abbas, Li Chen, Lauren M Sparks, Theresa Mau, Russell T Hepple, Karyn A Esser, Yenisel Cruz-Almeida.

High-impact musculoskeletal pain (i.e., pain that limits daily activities and function) affects a substantial proportion of older adults and is associated with accelerated mobility decline. While skeletal muscle is central to movement and functional capacity, its molecular contribution to pain-related disability in aging remains poorly understood. We conducted a cross-sectional analysis of baseline data from 742 community-dwelling adults aged 70 years or older from the Study of Muscle, Mobility and Aging (SOMMA). Bulk RNA sequencing was performed on vastus lateralis muscle biopsies. Pain impact was classified using self-reported pain and limitations in activities of daily living. Differential gene expression was examined comparing high-impact pain, low-impact pain, and no pain, with sex-stratified analyses. Pathway enrichment analyses were conducted to identify biological processes associated with high-impact pain. High-impact musculoskeletal pain was associated with a distinct skeletal muscle transcriptomic profile, whereas minimal differences were observed between low-impact pain and no pain. Sex-stratified analyses revealed substantial differences in pain-related gene expression for men and women. In men, high-impact pain was characterized by enrichment of musculoskeletal structural and extracellular matrix pathways. In women, high-impact pain was associated with broader transcriptional alterations involving immune, inflammatory, metabolic, and cytoskeletal processes. High-impact musculoskeletal pain in older adults was associated with sex-dependent skeletal muscle transcriptomic signatures distinct from those observed in low-impact pain. These findings implicate muscle-specific molecular pathways in pain-related functional limitations and highlight the importance of sex-informed approaches to understanding and treating chronic pain in aging.

Keywords: Chronic Pain; Gene Expression Profiling; Mobility Limitations; Older Adults; Sex Factors

DOI: https://doi.org/10.1177/17448069261499172

MicroPubl Biol. 2026 ;2026

Targeting Muscle-Specific E3 Ligases in Cancer Cachexia Through Structure-Based Virtual Screening of Small-Molecule Inhibitors.

Irfana Muqbil, Jordan D Johnson.

Cachexia is a multifactorial metabolic syndrome characterized by severe skeletal muscle loss that cannot be reversed by nutritional support. Common in cancer and other chronic diseases, it significantly increases morbidity and mortality. Muscle wasting is primarily driven by activation of the ubiquitin-proteasome pathway through the E3 ubiquitin ligases MuRF1 and Atrogin-1, which promote protein degradation and muscle atrophy. This study used computational modeling and docking to identify small-molecule inhibitors targeting these ligases, including repurposed drugs with anti-cachectic potential. Thalidomide and EM12-So2F were prioritized based on integrated docking, binding affinity, and drug-likeness/ADME analyses for validation in C2C12 myotube-based cachexia models.

DOI: https://doi.org/10.17912/micropub.biology.002256

Traffic. 2026 Dec;27(4): e70056

The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Alexis Diaz Vegas, Thierry Galli.

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Puszynska and colleagues now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis. The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders and vulnerability to late-onset neurodegeneration.

DOI: https://doi.org/10.1111/tra.70056

Nat Commun. 2026 09 18. pii: 10949. [Epub ahead of print]17(1):

Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.

Blanca Majem, Min-Sik Lee, Kyung Cheul Shin, Insia Naqvi, Courtney Dennis, Lucas Dailey, Sarah Jeanfavre, Mari Mino-Kenudson, Joao B Xavier, Clary B Clish, Deepti Mathur, Nada Y Kalaany.

Cachexia or body wasting is a significant contributing factor to the morbidity and mortality of pancreatic cancer. Despite an unmet need, its metabolic underpinnings remain poorly understood. Here, we characterize a mouse model that recaptures the longitudinal progression of human cachexia during pancreatic cancer development. We profile the metabolomes of pre-, early- and late-stage cancer-associated cachexia in male and female pancreas, its interstitial fluid (IF), plasma, liver, adipose tissue and skeletal muscle. We find that each tissue has a unique metabolome and trajectory across stages and reveal a marked lipid enrichment in the tumor IF. Using mathematical modeling, we identify metabolites participating in cross-tissue networks and in vivo validate a lactate-glucose conversion. We find systemic metabolic changes prior to weight loss and use feature selection algorithms to identify early detection markers. Our study provides a resource for system-wide metabolic evolution of pancreatic cancer and associated cachexia, highlighting the potential for timely diagnostics and interventions.

DOI: https://doi.org/10.1038/s41467-026-77745-0

J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70407

Integrated Single-Myofibre Multi-Omics Correlates Inflammatory State to Myosin Energetics in ICU-Acquired Weakness.

Alexandra M Winant, Roger Moreno-Justicia, Lucia Paolini, Wout J Claassen, Coen A C Ottenheijm, Atul S Deshmukh, Stefano Cattaneo, Simone Piva, Nicola Latronico, Robert A E Seaborne, Julien Ochala.

BACKGROUND: Skeletal muscle atrophy is a pervasive complication of critical illness that worsens survival and recovery, yet remains poorly explained by current clinical or molecular markers.
METHODS: To directly connect disease-associated molecular states to the contractile machinery, this study combined sequential functional, transcriptomic and proteomic profiling of the same single human skeletal myofibres from critically ill patients in the intensive care unit with acquired weakness (ICU-AW) and controls. This integrated approach provides a framework for validating molecular signals directly within the cellular and biomechanical context.
RESULTS: Differential expression analyses between control and ICU-AW myofibres show marked donor-level heterogeneity, with no differentially expressed features (FDR < 0.05). Ranked gene set enrichment analyses revealed distinct transcriptional and proteomic signatures between conditions, as well as a subtle yet conserved myofibre state enriched in ICU-AW, characterised by inflammatory and chemotactic gene programmes, intracellular structural remodelling and bioenergetic adaptation. Nineteen features were significantly (FDR < 0.05) altered at both RNA and protein levels from the same myofibre. Overall, these 19 overlapping features link an inflammatory transcriptional landscape to a proteomic shift toward mitochondrial and translational machinery, revealing a coordinated stress-adaptation programme with selective post-translational control in fibres from patients with ICU-AW. Further integration with the functional dataset revealed fibres in this state displayed selectively disrupted myosin dynamics, evidenced by prolonged ATP turnover time of myosin heads in their super-relaxed conformation, suggesting altered myosin energetics as a contributor to muscle dysfunction.
CONCLUSIONS: These findings define a discrete, disease-associated myofibre state and validate a proof-of-concept integrative single-fibre framework for connecting multi-omic heterogeneity to molecular motor function in complex human disease. The identification of coordinated transcriptomic and proteomic programmes, validated through functional measurement, suggests that targeting this fibre state may offer new therapeutic opportunities in ICU-acquired dysfunction and related muscle disorders.

Keywords: critical illness; multi‐omics; muscle weakness; myosin energetics; single‐fibre analysis; skeletal muscle heterogeneity

DOI: https://doi.org/10.1002/jcsm.70407

Aging Cell. 2026 Nov;25(11): e70745

A Cilia-Centered Nicotinamide Adenine Dinucleotide (NAD+) Signaling Network Regulates Hypothalamic Lysosomal Homeostasis and Metabolic Aging.

Se Eun Park, Eun Roh, Jae Woo Park, Seong Jun Kim, So Yeon Jeong, Chae Beom Park, Hyo Sun Lim, Ji Soo Kim, Mun Gyeom Kim, Myeong Ju Kim, Young In Cho, Wontae Jeong, Gil Myoung Kang, Sang-Yeob Kim, Se Hee Min, Min-Seon Kim.

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that regulates diverse cellular metabolic processes. Primary cilia, hair-like organelles on the cell surface, function as critical signaling hubs. Here, we demonstrate that cellular NAD+ levels are key regulators of both primary cilia growth and lysosomal function in hypothalamic neurons. NAD+ depletion induces ciliary shortening and diminishes lysosomal activity in a cilia-dependent manner. Mechanistically, the lysosomal repair complex protein CHMP4B translocates from periciliary satellites to lysosomes during lysosomal stress, a process impaired by ciliary dysgenesis. Disrupted lysosomal recruitment of CHMP4B leads to abnormal lysosomal Ca2+ signaling and lysosomal dysfunction. Aged mice with hypothalamic NAD+ deficiency exhibit shortened cilia and lysosomal stress phenotypes, both of which are restored by calorie restriction (CR). Moreover, CR improves aging-associated metabolic dysfunction, at least in part, through hypothalamic cilia-dependent mechanisms. These findings identify a primary cilium-mediated-NAD+ signaling axis that maintains lysosomal homeostasis in hypothalamic neurons, the disruption of which drives metabolic aging.

Keywords: CHMP4B; NAD+; TRPML1; aging; calorie restriction; hypothalamic neurons; lysosomal homeostasis; primary cilia

DOI: https://doi.org/10.1111/acel.70745