The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance of solute carrier family 7 member 11 (SLC7A11) in inflammation and metabolism. Nevertheless, whether SLC7A11 regulates NASH progression through mediating inflammation and metabolism is unclear. In this study, we found that SLC7A11 expression was increased in liver samples from patients with NASH. Upregulated SLC7A11 level was also detected in two murine NASH models. Functional studies showed that SLC7A11 knockdown or knockout had augmented steatohepatitis with suppression of inflammatory markers in mice. However, overexpression of SLC7A11 dramatically alleviated diet-induced NASH pathogenesis. Mechanically, SLC7A11 decreased reactive oxygen species (ROS) level and promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, SLC7A11 impaired expression of NLRP3 inflammasome components through AMPK-mitophagy axis. IL-1β release through NLRP3 inflammasome recruited myeloid cells and promoted hepatic stellate cells (HSCs) activation, which contributed to the progression of liver injury and fibrosis. Anti-IL-1β and anakinra might attenuate the hepatic inflammatory response evoked by SLC7A11 knockdown. Moreover, the upregulation of SLC7A11 in NASH was contributed by lipid overload-induced JNK-c-Jun pathway. In conclusions, SLC7A11 acts as a protective factor in controlling the development of NASH. Upregulation of SLC7A11 is protective by regulating oxidation, αKG and energy metabolism, decreasing inflammation and fibrosis.

Background Gasdermin D (GSDMD) is well known as a downstream of inflammasomes. However, the roles of GSDMD itself in hepatocellular carcinoma (HCC) remain unclear. Methods Two independent cohorts of patients with HCC were analyzed to evaluate the pathological relevance of GSDMD/pTBK1/PD-L1. GSDMD knockout (GSDMD-/-) mice, Alb-Cre mice administered with an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and their wild-type littermates were used to induce hepatocarcinogenesis or metastatic HCC. Combination of anti-programmed cell death protein-1 (PD-1) and GSDMD inhibitor dimethyl fumarate (DMF) was used to test for improved therapeutic efficacy. RNA sequencing was used to explore the mechanisms how GSDMD promoted HCC progression. Results The expression of GSDMD and GSDMD-N was upregulated in HCC tissues or metastatic HCC tissues and positive GSDMD expression indicated grim prognosis. Diethylnitrosamine/carbon tetrachloride or thioacetamide-treated GSDMD-/- mice exhibited decreased liver tumors. In contrast, AAV9-FLEX-GSDMD-N promoted hepatocarcinogenesis. RNA sequencing manifested that knockout of GSDMD impacted the cyclic GMP-AMP synthase (cGAS) pathway and immune-associated pathway. GSDMD damped cGAS activation by promoting autophagy via outputting potassium (K+) and promoted programmed death ligand-1 (PD-L1) expression by histone deacetylases/signal transducer and activator of transcription 1 (STAT1)-induced transactivation of PD-L1 via importing calcium (Ca2+). High Mobility Group Box 1/toll-like receptor 4 (TLR4)/caspase-1 pathway contributed to the overexpression and cleavage of GSDMD. Anti-PD-1 combining with DMF largely impaired HCC progression and metastasis. Conclusions Targeting GSDMD could promote expression of interferons through inactivation of cGAS pathway and downregulated the PD-L1 expression. Therefore, combined anti-PD-1 and GSDMD inhibitor might serve as an effective treatment option for patients with HCC with GSDMD upregulation.

Background and Aims: In December 2019, an outbreak of coronavirus disease 2019 (COVID‐19) emerged in Wuhan, China. Although it has been reported that some patients with COVID‐19 showed elevated liver biochemistries, there are few studies regarding the clinical features and prognosis of these patients. Approach and Results: In this multicenter, retrospective study, we collected data on laboratory‐confirmed patients with COVID‐19 from three hospitals in Wuhan, China, who died or were discharged between February 1, 2020, and February 20, 2020. Data on demographics, comorbidities, clinical symptoms, laboratory examinations on admission, complications, treatment, and outcome were collected. A total of 482 patients were enrolled in this study. Of those, 142 (29.5%) patients showed abnormal liver biochemistries on admission, and patients with elevated alanine aminotransferase, aspartate aminotransferase (AST), and total bilirubin (TBIL) accounted for 67.6%, 69.0%, and 16.2%, respectively. Those with abnormal liver biochemistries showed higher percentages of severe cases and comorbidities and were more likely to have dyspnea, chest distress or pain, and increased hemoglobin (Hb) on admission. Higher rates of complications and mortality and worse recovery when discharged were observed in patients with abnormal AST or TBIL. Multivariable regression analysis showed that chest distress or pain (odds ratio [OR], 1.765; P = 0.018), dyspnea (OR, 2.495; P = 0.001), elevated C‐reactive protein level (OR, 1.007; P = 0.008), elevated white blood count (OR, 1.139; P = 0.013), and elevated Hb concentration (OR, 1.024; P = 0.001) were independent factors associated with elevated liver biochemistries in patients with COVID‐19. Conclusions: Elevated liver biochemistries were common in patients with COVID‐19. Patients with hypoxia or severe inflammation are more likely to experience increased liver biochemistries on admission. Those with abnormal AST or TBIL on admission are more likely to suffer from severe complications and death.

Purpose: BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and α-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for β-genus HPV is suspected in BRAFi-cSCC. Cutaneous β-HPV may act in concert with host and environmental factors in BRAFi-cSCC. Experimental Design: Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology. Results: Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, β-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel β-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected. Conclusions: We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; β-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered β-HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general. Clin Cancer Res; 21(11); 2624–34. ©2015 AACR.