Hormones play a central role in regulating cellular metabolism in many tissues, including the liver (Brubaker and Martchenko, 2022). Disruptions in hormone signaling are closely linked to the hepatic manifestation of metabolic syndrome (MetS), collectively referred to as metabolic dysfunction-associated steatotic liver disease (MASLD) (Hutchison et al., 2023; Loria et al., 2009; Marino and Jornayvaz, 2015). Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a severe and advanced stage of MASLD that can lead to liver failure. MASH is characterized by hepatic steatosis, persistent inflammation, hepatocellular injury, and progressive fibrosis, which may ultimately progress to cirrhosis and hepatocellular cancer (Habibullah et al., 2024; Hagström et al., 2024; Matchett et al., 2024). The increasing prevalence of MASLD/MASH as a liver disease of metabolic origin, driven by conditions such as obesity, type 2 diabetes, and dyslipidemia, has led to serious global public health problems (Cooreman et al., 2024; Tincopa et al., 2024; Zannad et al., 2024). Despite the growing medical and economic burden of this disease, there are few effective therapeutic strategies to halt or reverse its progression (Cooreman et al., 2024; Tincopa et al., 2024; Zannad et al., 2024).

The induction of autophagy through pharmacological or non-pharmacological methods has recently attracted significant attention as a potential anti-MASH strategy (Chen and Lin, 2022). Autophagy, derived from the Greek term "self-eating," is a lysosome-mediated catabolic process by which cells degrade and recycle their constituents to maintain cellular homeostasis (Vargas et al., 2023). Mammalian cells have four primary forms of autophagy: macroautophagy, microautophagy, chaperone-mediated autophagy (CMA), and crinophagy (Vargas et al., 2023). Of these, macroautophagy, hereafter simply referred to as autophagy, entails the formation of a phagophore that sequesters cytoplasmic "cargo" such as damaged organelles, proteins, or other cellular components. Subsequently, the phagophore expands and matures into a closed autophagosome structure. The autophagosome then fuses with lysosomes to form autolysosomes, which degrade the cargo contents by acid hydrolases and lipases to facilitate the breakdown and renewal of cellular materials to maintain energy and metabolic homeostasis (Vargas et al., 2023). Both preclinical and clinical studies have demonstrated significant correlations between the severity of MASH and impaired autophagy in the liver (Gonzalez-Rodriguez et al., 2014; Inami et al., 2011; Jonas et al., 2022; Wang et al., 2018). Furthermore, restoration of autophagic function alleviated hepatic steatosis and promoted resolution of hepatic inflammation, apoptosis, and fibrosis (Raza et al., 2024). These findings highlight the potential of autophagy modulation as a therapeutic strategy for MASH in humans (Raza et al., 2024; Sinha, 2023). We and others have shown that hormones such as thyroid hormone, epinephrine, and glucagon are potent autophagy inducers in the liver that function through genomic and non-genomic signaling pathways (Sinha et al., 2017). Of note, Resmetirom, a liver-specific thyroid hormone analogue, enhanced hepatic autophagy like endogenous thyroid hormones (Sinha, 2024; Sinha, Bruinstroop and Yen, 2024), and recently was approved as the first pharmacological treatment for MASH.

A high prevalence of adrenal failure has been found in patients with advanced liver disease and those undergoing liver transplantation. This association suggested there was a potential interplay between adrenal and liver (Wentworth and Siragy, 2022) as decreased adrenal function could have a deleterious effect on liver disease. Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, are primarily synthesized in the adrenal cortex and are among the most abundant endogenous steroid hormones. DHEA either directly or via its metabolite has been shown to bind to estrogen receptors (ER) and androgen receptors (AR) (Chen et al., 2005); (Miller et al., 2013). DHEA exerts an immunomodulatory and metabolic regulatory property, as lower levels of DHEA and DHEA-S are associated with histologically advanced NASH. In addition, reduced circulating levels of DHEA-S are strongly correlated with severe fibrosis in patients with NASH (Koehler et al., 2012; Koga et al., 2011; Li et al., 2021; Sumida et al., 2010). DHEA has also been previously reported to induce autophagy in primary chicken hepatocytes and human hepatoma cells (Yao et al., 2023); (Vegliante et al., 2016). However, the mechanism by which DHEA regulates hepatic autophagy in hepatocytes, and the therapeutic potential of DHEA administration in human MASH are not completely understood. In this study, we demonstrated that DHEA acts as a potent inducer of autophagy in hepatic cells both in vitro and in vivo. Mechanistic investigations revealed that DHEA mitigated lipotoxicity-induced hepatic damage and inflammatory signaling by promoting Erα/AR-mediated autophagy and resolving MASH in animal models.