By combining gene expression analysis in liver biopsies with in vitro investigations in cultured hepatocytes, we provide the first evidence suggesting a possible role of TAOK1 in the development and progression of NAFLD through mediating fatty acid channeling between anabolic and catabolic pathways, regulating oxidative/endoplasmic reticulum (ER) stress, and modulating metabolic and pro-oncogenic signaling pathways. Here, TAOK1 is linked to metabolic dysfunction-associated steatotic liver disease.