The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

Fisetin protects against high fat diet-induced nephropathy by inhibiting inflammation and oxidative stress via the blockage of iRhom2/NF-κB signaling.

Promoted inflammation enhances the development of nephropathy in obesity. Fisetin (3,3',4',7-tetrahydroxyflavone, FIS) is a naturally occurring dietary flavonoid, and exhibits anti-inflammatory and anti-oxidative properties. Inactive rhomboid protein 2 (iRhom2), an inactive member of the rhomboid intramembrane proteinase family, is an essential inflammation-associated regulator. Here, we attempted to investigate the protective mechanisms of FIS against high fat diet (HFD)-induced nephropathy, with particular focus on iRhom2. We found that HFD induced systematic and renal pro-inflammatory cytokine production. Furthermore, iRhom2 expression was markedly elevated in kidney of HFD-fed mice, and in PAL-incubated macrophages, accompanied with high phosphorylation of NF-κB. Significant oxidative stress was observed in kidney of HFD-fed mice through suppressing Nrf-2/HO-1 signaling. Moreover, activation of iRhom2/NF-κB signaling and oxidative stress by PAL was detected in macrophages, which were effectively reversed by FIS. Importantly, we showed that iRhom2 knockdown significantly abrogated the ability of FIS to restrain inflammation and oxidative stress induced by PAL in macrophages, indicating that iRhom2 might be a potential therapeutic target for FIS during nephropathy treatment. Together, these results revealed that FIS could mitigate HFD-induced renal injury by regulating iRhom2/NF-κB and Nrf-2/HO-1 signaling pathways.