Asprosin-driven metabolic-epigenetic rewiring attenuates mesenchymal stem cell senescence with therapeutic benefits for infarcted hearts

INTRODUCTION: Senescent mesenchymal stem cells (MSCs) exhibit impaired self-renewal, limiting their therapeutic potential. While multi-omics have revealed downregulation of pan-tissue Fbn1 with aging, particularly in MSCs, the role of its derivative asprosin in MSC senescence is unknown. OBJECTIVES: To elucidate the regulation of senescence/reparative function in aged MSCs by asprosin and evaluate its therapeutic potential for aged MSC-mediated cardiac repair after myocardial infarction (MI). METHODS: Serum asprosin levels were measured by enzyme-linked immunosorbent assay, and asprosin expression in MSCs was determined by western blotting. Fbn1 expressiondynamics with aging were assessed using public transcriptomic/single-cell datasets. Gain/loss-of-function (lentiviral overexpression/CRISPR-Cas9 knockout) studies were employed to validate the role of asprosin. The effects of recombinant asprosin on senescent MSC proliferation, migration, and pro-angiogenic secretion were tested. Glycolytic flux (Seahorse), metabolites (glucose uptake, G-6-P, lactate), and lactylation (pan-lysine, H3K18la) were measured. Integrated H3K18la CUT&Tag/RNA-seq was performed to identify downstreamtargets, and therapeutic efficacy was assessed in an MI mouse model using intramyocardial injection of asprosin-overexpressing aged MSCs. RESULTS: Circulating asprosin was correlated with adipose mass in young obese mice but was attenuated in aged obese mice. Consistently, human cohorts (normal body mass index) showed an inverse age-asprosin correlation. Systemic and MSC-specific asprosin expression significantly declined with aging. Asprosin knockout intensified H₂O₂-induced MSC acute premature senescence, whereas its overexpression restored MSC self-renewal. Human recombinant asprosin protein (requiring post-translational modifications for bioactivity) enhanced proliferation, migration, and paracrine angiogenesis in senescent MSCs. Mechanistically, asprosin activated the PI3K/Akt-HIF-1 pathway to upregulate VEGF/TIMP1 (angiogenesis) and drive the glycolysis-lactate-H3K18la axis (proliferation/migration). H3K18la CUT&Tag/RNA-seq identified targets regulating DNA repair, proliferation, and migration. Asprosin deficiency impaired DNA repair. In MI mice, asprosin-overexpressing aged MSCs significantly improved retention and left ventricular ejection fraction, attenuated cardiac remodeling, and promoted peri-infarct angiogenesis. CONCLUSION: Asprosin is a novel MSC-specific rejuvenation factor that antagonizes senescence through metabolic-epigenetic interplay. Targeting the asprosin-driven "Glycolysis-Lactylation-Epigenetics" axis offers a transformative strategy to enhance MSC-based therapies for ischemic heart disease.