Bello, F. | bioRxiv Science

bioRxiv2026

Dynamic zonal identity is a functional determinant of liver disease

Liver zonation demarcates functional division of labor within the hepatic lobule, yet how zonal identity is reshaped during disease remains poorly understood. We developed RIZLiver, a Bayesian framework that infers zonal identity from gene expression without spatial coordinates. RIZLiver identified progressive loss of zone-3 metabolic identity with advancing stages of metabolic dysfunction-associated steatotic liver disease (MASLD) across independent patient cohorts. Complementary mouse models reveal that perturbing zonal identity shifts susceptibility to diet-induced metabolic injury, linking zone-3 identity to adaptive lipid utilization through lower case beta-catenin and PPARalpha. CTNNB1-mutated hepatocellular carcinomas (HCC) showed an enriched zone-3 and lipid-oxidative phenotype, extending metabolic perturbations beyond MASLD. Pharmacologic reactivation of the zone-3 program shows a therapeutic effect in MASLD. Conversely, interfering with lipid-metabolic addiction in CTNNB1-mutated HCC by targeting PPARalpha; yielded a therapeutic benefit. Our findings identify zonation as a dynamic component of disease phenotype and its restoration as a potential therapy.

molecular biology↗

bioRxiv2025

Exercise-Induced Myostimulin Enhances Muscle Function in Health and Disease

Musculoskeletal diseases are a leading contributor to years lived with disability worldwide1,2. While exercise offers significant benefits for people with these conditions, many individuals do not engage in adequate physical activity3. Consequently, there is growing interest in pharmacological interventions that can emulate essential health-promoting effects of exercise4,5. By integrating transcriptomics data of exercised skeletal muscle, we identified C1orf54/C1ORF54 as a novel exercise-responsive gene in mice and humans. We demonstrate that removal of the first sixteen N-terminal amino acids of C1ORF54 gives rise to a previously uncharacterized protein that stimulates the proliferation of muscle precursor cells and which we named myostimulin. Intriguingly, repeated intermittent treatment of mice with recombinant myostimulin boosts maximal isometric strength in mice within a week. Moreover, we have engineered a variant with improved biophysical properties, increased biological activity in vitro and enhanced efficacy in vivo. This variant even accelerates the recovery of muscle strength from axonotmesis, a condition associated with pronounced muscle weakness. Our data ascribe to myostimulin a role for enhancing the regenerative capacity of skeletal muscle and mediating functional adaptations characteristic of sustained resistance training. Therefore, myostimulin could be an innovative, fast acting therapeutic for certain human musculoskeletal diseases, injuries and other disorders that improve with exercise.

physiology↗