Thyroid Hormone-Mediated Selective Autophagy and Its Implications in Countering Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum.

Keywords: 3,5-Diiodothyronine; Autophagy; Metabolic dysfunction-associated steatohepatitis; Metabolic dysfunction-associated steatotic liver disease; Mitophagy; Resmetirom; Thyroid hormones.

Fig. 1.

Potential role of thyroid hormone (TH)-induced selective autophagy in mitigating metabolic dysfunction-associated steatotic liver disease (MASLD) progression. TH-induced selective autophagy, which includes lipophagy, mitophagy, and aggrephagy, may influence various stages of MASLD progression, from benign steatosis to hepatocellular carcinoma (HCC) development. Specifically, lipophagy may help prevent the accumulation of lipids within hepatocytes, thereby preventing the onset of MASLD. In contrast, TH-induced mitophagy induction may play a pivotal role in preserving mitochondrial health and limiting inflammation, both of which are essential in averting the progression to metabolic dysfunction-associated steatohepatitis (MASH). Finally, TH-induced aggrephagy during MASH could act as a key anti-neoplastic mechanism in hepatocytes. These cells are susceptible to protein aggregate accumulation, which increases proteotoxicity and genotoxicity that can lead to HCC development.