Transcription factor 19 modulates fatty acid elongation and unfolded protein response to attenuate palmitic acid-induced hepatic dysfunction

Saturated fatty acids, which increase during high-fat diets and metabolic disease, disrupt lipid homoeostasis, leading to hepatic dysfunction. Understanding how hepatocytes adapt to this stress is essential for delineating the early events of fatty liver disease and its progression to more severe inflammation and fibrosis. Here, we show that the transcription factor TCF19 acts as a central regulator that helps hepatocytes manage lipid overload and cellular stress in both MAFLD mice model and human clinical samples. Combining lipidomic and transcriptomic analysis, we found that TCF19 controls genes involved in fatty-acid elongation and protein-folding responses, thereby linking lipid metabolism with endoplasmic-reticulum stress-response pathways. Elevated TCF19 levels are associated with lipid accumulation, whereas reducing TCF19 worsens inflammation and fibrotic features of the liver. Together, our findings identify TCF19 as a protective regulator during the transition from early hepatic fat accumulation to inflammatory liver disease, highlighting a potential target for early therapeutic intervention.