Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets.

Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames within mitochondrial DNA (mtDNA). Humanin, the first MDP to be discovered, functions as a cytoprotective factor, protecting cells from stress-induced apoptosis. Subsequent discoveries expanded this family to include Mitochondrial Open-reading-frame of the Twelve S rRNA-c (MOTS-c), a key regulator of metabolic homeostasis and stress adaptation, and the Small Humanin-Like Peptides (SHLP1-6), which modulate mitochondrial bioenergetics and insulin sensitivity. MDPs play critical roles in liver homeostasis by maintaining mitochondrial function and metabolic balance. Intracellularly, they modulate mitochondrial activity, oxidative stress, and apoptosis, promoting hepatocyte survival. Extracellularly, they act in autocrine, paracrine, or endocrine manners, engaging receptors or signaling pathways to regulate nuclear gene expression and metabolic adaptation. Emerging evidence highlights their relevance in metabolic dysfunction-associated steatotic liver disease (MASLD). Humanin exerts hepatoprotective effects by inhibiting apoptosis and modulating lipid metabolism. MOTS-c activates AMPK, regulates nuclear gene expression, suppresses fibrotic and inflammatory signaling, and restores mitochondrial function in MASLD and fibrosis models. SHLPs, particularly SHLP2, enhance mitochondrial function and insulin sensitivity, supporting glucose homeostasis and mitigating oxidative stress. Collectively, MDPs establish a novel paradigm in mitochondrial signaling, extending mtDNA function beyond energy production. This review summarizes current insights into MDP biology and highlights its emerging therapeutic potential in chronic liver disease.