Remote limb ischemic conditioning alleviates steatohepatitis via extracellular vesicle-mediated muscle-liver crosstalk

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of liver disease with adverse outcomes. Manipulating interorgan communication is considered a promising strategy for managing metabolic disease, including steatohepatitis. Here, we report that remote limb ischemic conditioning (RIC), a clinically validated therapy for distant organ protection by transient muscle ischemia, significantly alleviated steatohepatitis in different mouse models. The beneficial effect of limb ischemic conditioning was mediated by muscle-to-liver transfer of small extracellular vesicles (sEVs) and their cargo microRNAs, leading to elevation of miR-181d-5p in the liver. Hepatic miR-181d-5p overexpression faithfully mirrored the molecular and histological benefits of limb ischemic conditioning by suppressing nuclear receptor 4A3 (NR4A3). Furthermore, circulating EVs from human volunteers undergoing limb ischemic conditioning improved steatohepatitis and transcriptomic perturbations in primary human hepatocytes and animal models. Our data underscore the translational potential of limb ischemic conditioning for steatohepatitis management and extend our understanding of muscle-liver crosstalk.