Background and Aims Nonalcoholic fatty liver disease (NAFLD) has been widely recognized as a precursor to metabolic complications. Elevated inflammation levels are predictive of NAFLD‐associated metabolic disorder. Inactive rhomboid‐like protein 2 (iRhom2) is regarded as a key regulator in inflammation. However, the precise mechanisms by which iRhom2‐regulated inflammation promotes NAFLD progression remain to be elucidated. Approach and Results Here, we report that insulin resistance, hepatic steatosis, and specific macrophage inflammatory activation are significantly alleviated in iRhom2‐deficient (knockout [KO]) mice, but aggravated in iRhom2 overexpressing mice. We further show that, mechanistically, in response to a high‐fat diet (HFD), iRhom2 KO mice and mice with iRhom2 deficiency in myeloid cells only showed less severe hepatic steatosis and insulin resistance than controls. Inversely, transplantation of bone marrow cells from healthy mice to iRhom2 KO mice expedited the severity of insulin resistance and hepatic dyslipidemia. Of note, in response to HFD, hepatic iRhom2 binds to mitogen‐activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and nuclear factor kappa B cascade activation, thereby promoting the activation of c‐Jun N‐terminal kinase/insulin receptor substrate 1 signaling, but disturbing AKT/glycogen synthase kinase 3β–associated insulin signaling. The iRhom2/MAP3K7 axis is essential for iRhom2‐regulated liver steatosis. Conclusions iRhom2 may represent a therapeutic target for the treatment of HFD‐induced hepatic steatosis and insulin resistance.

PM2.5 is a well-known air pollutant threatening public health, and long-term exposure to PM2.5 increases the risk of cardiovascular diseases. Nrf2 plays a pivotal role in the amelioration of PM2.5-induced lung injury. However, if Nrf2 is involved in PM2.5-induced heart injury, and the underlying molecular mechanisms have not been explored. In this study, wild type (Nrf2 +/+) and Nrf2 knockout (Nrf2-/-) mice were exposed to PM2.5 for 6 months. After PM2.5 exposure, Nrf2-/mice developed severe physiological changes, lung injury and cardiac dysfunction. In the PM2.5-exposed hearts, Nrf2 deficiency caused significant collagen accumulation through promoting the expression of fibrosis-associated signals. Additionally, Nrf2-/mice exhibited greater oxidative stress in cardiac tissues after PM2.5 exposure. Furthermore, PM2.5-induced inflammation in heart samples were accelerated in Nrf2-/mice through promoting inhibitor of α/nuclear factor κB (IκBα/NF-κB) signaling pathways. We also found that Nrf2-/aggravated autophagy initiation and glucose metabolism disorder in hearts of mice with PM2.5 challenge. Cardiac receptor-interacting protein kinase 3 (RIPK3) expression triggered by PM2.5 was further enhanced in mice with the loss of Nrf2. Collectively, these results suggested that strategies for enhancing Nrf2 could be used to treat PM2.5-induced cardiovascular diseases.

Air pollution containing particulate matter (PM) less than 2.5 μm (PM 2.5 ) plays an essential role in regulating hepatic disease. However, its molecular mechanism is not yet clear, lacking effective therapeutic strategies. In this study, we attempted to investigate the effects and mechanisms of PM 2.5 exposure on hepatic injury by the in vitro and in vivo experiments. At first, we found that PM 2.5 incubation led to a significant reduction of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), along with markedly reduced expression of different anti-oxidants. Notably, suppressor of IKKε (SIKE), known as a negative regulator of the interferon pathway, was decreased in PM 2.5 -incubated cells, accompanied with increased activation of TANK-binding kinase 1 (TBK1) and nuclear factor-κB (NF-κB). The in vitro studies showed that Nrf2 positively regulated SIKE expression under the conditions with or without PM 2.5 . After PM 2.5 treatment, Nrf2 knockdown further accelerated SIEK decrease and TBK1/NF-κB activation, and opposite results were observed in cells with Nrf2 over-expression. Subsequently, the gene loss- and gain-function analysis demonstrated that SIKE deficiency further aggravated inflammation and TBK1/NF-κB activation caused by PM 2.5 , which could be abrogated by SIKE over-expression. Importantly, SIKE-alleviated inflammation was mainly dependent on TBK1 activation. The in vivo studies confirmed that SIKE- and Nrf2-knockout mice showed significantly accelerated hepatic injury after long-term PM 2.5 exposure through reducing inflammatory response and oxidative stress. Juglanin (Jug), mainly isolated from Polygonum aviculare , exhibits anti-inflammatory and anti-oxidant effects. We found that Jug could increase Nrf2 activation, and then up-regulated SIKE in cells and liver tissues, mitigating PM 2.5 -induced liver injury. Together, all these data demonstrated that Nrf2 might positively meditate SIKE to inhibit inflammatory and oxidative damage, ameliorating PM 2.5 -induced liver injury. Jug could be considered as an effective therapeutic strategy against this disease by improving Nrf2/SIKE signaling pathway.

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