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USP13 Stabilizes SOX9 to Promote Metabolic Dysfunction-Associated Fatty Liver Disease and Liver Cancer Stem Cell Phenotype

ABSTRACT: Deregulation of SOX9 has been linked with metabolic diseases, self-renewal and cancer. SOX9, a master regulator of cell growth, can be regulated by a diverse set of Post-Translational Modifications (PTMs), including ubiquitylation. This study aims to elucidate the mechanisms that govern SOX9 protein stability that is mediated by the ubiquitin-proteasome system. Following a screen of the deubiquitinase library, SOX9 protein abundance was found to be regulated by ubiquitin-specific peptidase 13 (USP13) which deubiquitylates SOX9 and inhibits its protein degradation. Additionally, USP13 attenuates FBXW7- and KEAP1-mediated ubiquitination and degradation of SOX9 by directly binding to the SOX9 K2 domain, which contains a critical ubiquitination residue-K249. Genetic deletion or pharmacological inhibition of USP13 markedly decreases the metabolic dysfunction-associated fatty liver disease (MAFLD) development, the stemness capacity of liver cancer cells and enhances its chemo-sensitivity. Overexpression of exogenous SOX9 in USP13 deficient cells restored liver cancer cells self-renewal capacity and tumorigenesis. Clinical analyses revealed that the USP13-SOX9 axis is associated with poor prognosis in human hepatocellular carcinoma (HCC) patients. Therefore, pharmacological interventions targeting USP13 may have therapeutic potential for the treatment of HCC and MAFLD prevalent diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274072 | GEO | 2025/11/12

REPOSITORIES: GEO

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Project description:Metabolic dysfunction–associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear. In a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumor inhibition upon dietary correction. Carcinogenesis begins during MAFLD, with tumor cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to turnover of liver cells but do not primarily target the tumor. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response—not merely immune activation—dictates whether tumors grow or regress, emphasizing the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming. These findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumor-hostile microenvironment, whereas tumor-directed approaches fail to remodel the TME. This underscores the need for tissue remodeling strategies in cancer prevention and treatment. Our study challenges the traditional view that the liver is purely tolerant to immune responses, revealing that it actively regulates immunity to maintain tissue health. We found that liver cancer (HCC) begins during fatty liver disease (MAFLD) but can be halted if immune cells—especially monocytes—restore tissue integrity. Instead of focusing solely on killing tumors, effective immunotherapy should harness the body’s natural ability to repair the liver, creating an environment where cancer cannot thrive. This discovery paves the way for innovative treatments that promote immune-driven tissue regeneration as a strategy for cancer prevention and therapy.

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USP13 Stabilizes SOX9 to Promote Metabolic Dysfunction-Associated Fatty Liver Disease and Liver Cancer Stem Cell Phenotype

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