Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)-associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.

Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E (PGE). PGE exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer. A novel signaling circuit involving RIPK3 and PGE enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy. http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg .

Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Even milder AKI has adverse consequences and could progress to renal fibrosis, which is the ultimate common pathway for various terminal kidney diseases. Thus, it is urgent to develop a strategy to hinder the transition from AKI to CKD. Some molecular mechanisms of AKI to CKD transition have been revealed, such as nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction and epigenetic changes. Previous studies have elucidated the pivotal role of mitochondria in acute injuries and demonstrated that the fitness of this organelle is a major determinant in both the pathogenesis and recovery of organ function. Recent research has suggested that damage to mitochondrial function in early AKI is a crucial factor leading to tubular injury and persistent renal insufficiency. Dysregulation of mitochondrial homeostasis, alterations in bioenergetics, and organelle stress crosstalk contribute to the AKI to CKD transition. In this review, we focus on the pathophysiology of mitochondria in renal recovery after AKI and progression to CKD, confirming that targeting mitochondria represents a potentially effective therapeutic strategy for the progression of AKI to CKD.

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Based on the active site structure and catalytic mechanism of SOD1, we developed a new type of efficient and specific SOD1 inhibitor which can directly change the intracellular levels of H2O2 and O2˙–.

Background/Aims: This study aimed to explore the metabololipidome in mice upon cupping treatment. Methods: A nude mouse model mimicking the cupping treatment in humans was established by administrating four cupping sets on the back skin for 15 minutes. UPLC-MS/ MS was performed to determine the PUFA metabolome in mice skin and blood before and after cupping treatment. The significantly changed lipids were administered in macrophages to assess the production of pro-inflammatory cytokines IL-6 and TNF-α by ELISA. Results: The anti-inflammatory lipids, e.g. PGE₁, 5,6-EET, 14,15-EET, 10S,17S-DiHDoHE, 17R-RvD1, RvD5 and 14S-HDoHE were significantly increased while pro-inflammatory lipids, e.g. 12-HETE and TXB₂ were deceased in the skin or plasma post cupping treatment. Cupping treatment reversed the LPS-stimulated IL-6 and TNF-α expression in mouse peritoneal exudates. Moreover, 5,6-EET, PGE₁ decreased the level of TNF-α, while 5,6-EET, 5,6-DHET downregulated IL-6 production in macrophages. Importantly, 14,15-EET and 14S-HDoHE inhibited both IL-6 and TNF-α induced by lipopolysaccharide (LPS). 17-RvD1, RvD5 and PGE₁ significantly reduced the LPS-initiated TNF-α, while TXB₂ and 12-HETE further upregulated the LPS-enhanced IL-6 and TNF-α expression in macrophages. Conclusion: Our results reveal the identities of anti-inflammatory versus pro-inflammatory metabolipidome and suggest the potential therapeutic mechanism of cupping treatment.

The dynamic expression of Fgl2 and RvDp5 synergistically programs inflammation resolution to restore homeostasis.

Background & Aims: Liver cancer stem cells (LCSCs) mediate therapeutic resistance and correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is unknown. Methods: LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays. Ca 2+ image was employed to determine the intracellular concentration of Ca 2+ . Gain- and loss-of function studies were applied to explore the role of FGF19 signaling in the self-renewal of LCSCs. Results: FGF19 was up-regulated in LCSCs, and positively correlated with certain self-renewal related genes in HCC. Silencing FGF19 suppressed self-renewal of LCSCs, whereas overexpressing FGF19 facilitated CSCs-like properties via activation of FGF receptor (FGFR)-4 in none-LCSCs. Mechanistically, FGF19/FGFR4 signaling stimulated store-operated Ca 2+ entry (SOCE) through both the PLCγ and ERK1/2 pathways. Subsequently, SOCE-calcineurin signaling promoted the activation and translocation of nuclear factors of activated T cells (NFAT)-c2, which transcriptionally activated the expression of stemness-related genes ( e.g., NANOG , OCT4 and SOX2 ), as well as FGF19 . Furthermore, blockade of FGF19/FGFR4-NFATc2 signaling observably suppressed the self-renewal of LCSCs. Conclusions: FGF19/FGFR4 axis promotes the self-renewal of LCSCs via activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.