Growth differentiation factor 15 mitigates lipotoxic steatosis by preserving mitochondrial morphodynamics and augmenting fatty acid oxidation in hepatocytes and liver organoids

Aims Growth differentiation factor 15 (GDF15) has emerged as a promising metabolic regulator with hepatoprotective properties in metabolic dysfunction‐associated steatotic liver disease (MASLD), yet its underlying mechanisms remain elusive. Given that mitochondria are the primary site of fatty acid oxidation (FAO) and that mitochondrial morphodynamics are critical for normal hepatic lipid metabolism, we investigated how GDF15 regulates hepatic lipid homeostasis through mitochondrial dynamics. Materials and Methods We established cellular steatosis models using primary rat hepatocytes exposed to lipotoxic palmitate (PA) or non‐lipotoxic free fatty acid mixture (FFA, oleate: palmitate = 2: 1). Following GDF15 administration, we quantified lipid droplet content, expression of lipid metabolism genes, mitochondrial fatty acid translocation, and mitochondrial morphodynamics and function. The mechanistic role of ERK1/2 signalling was assessed through pharmacological inhibition. These findings were subsequently validated in adult progenitor cell‐derived human liver organoids. Results GDF15 significantly mitigated both PA‐ and FFA‐induced lipid accumulation by upregulating key FAO genes and down regulating lipid synthesis genes. Importantly, GDF15 corrected PA‐induced mitochondrial fusion‐fission imbalance by increasing mitochondrial fusion proteins MFN1 and OPA1 while modulating the activation of fission regulator DRP1. GDF15 enhanced fatty acid translocation into mitochondria and improved FAO. Mechanistically, GDF15 exerted these effects partially through inhibition of the ERK1/2 signalling pathway. Human liver organoid models further corroborated this protective mechanism of GDF15 against hepatic steatosis. Conclusions Our study reveals that, specifically under lipotoxic conditions, GDF15 alleviates hepatocyte steatosis by preserving mitochondrial morphodynamics homeostasis and enhancing mitochondrial FAO capacity via ERK1/2 inhibition. These condition‐specific mechanisms provide critical insights into GDF15's hepatoprotective effects and support its further investigation as a potential therapeutic target for MASLD.