Protein phosphatase 6 (PP6) is a serine/threonine phosphatase involved in diverse cellular processes. A recent study using a diet-induced metabolic dysfunction-associated steatohepatitis (MASH) model has shown that PP6 regulates hepatic pathology via mammalian target of rapamycin complex 1 (mTORC1) signaling; however, the role of PP6 in liver homeostasis under physiological conditions has not been systematically examined. Here, we demonstrate that hepatocyte-specific Ppp6c-deficient (PP6 HKO) mice develop spontaneous liver abnormalities under chow-fed conditions, including hepatomegaly, elevated serum liver injury markers, hepatocellular swelling, apoptosis, and inflammatory cell infiltration. Transcriptomic analyses revealed marked suppression of mitochondrial pathways, particularly oxidative phosphorylation, along with enrichment of inflammatory, apoptotic, and mTORC1 signaling pathways. Ultrastructural analyses further showed disrupted mitochondrial cristae and expansion of the rough endoplasmic reticulum in PP6-deficient hepatocytes, accompanied by increased expression of ER and oxidative stress markers. Mechanistically, PP6 loss led to sustained hyperactivation of the Akt/mTOR pathway, as evidenced by increased phosphorylation of Akt and mTOR and induction of downstream targets, independent of ERK signaling. Persistent Akt/mTOR activation was associated with mitochondrial dysfunction, cellular stress responses, and hepatocyte injury. Collectively, these findings identify PP6 as a critical regulator of hepatocyte homeostasis under physiological conditions by restraining Akt/mTOR signaling.
