Hypoxia is an important factor in the development of synovitis in rheumatoid arthritis (RA). The previous study of the research group found that monomeric derivatives of paeoniflorin (MDP) can alleviate joint inflammation in adjuvant‐induced arthritis (AA) rats by inhibiting macrophage pyroptosis. This study revealed increased levels of hypoxia‐inducible factor‐ (HIF‐) 1α and N‐terminal p30 fragment of GSDMD (GSDMD‐N) in fibroblast‐like synoviocytes (FLS) of RA patients and AA rats, while MDP significantly inhibited their expression. Subsequently, FLS were exposed to a hypoxic environment or treated with cobalt ion in vitro. Western blot and immunofluorescence analysis showed increased expression of G protein‐coupled receptor kinase 2 (GRK2), HIF‐1α, nucleotide‐binding oligomerization segment‐like receptor family 3 (NLRP3), ASC, caspase‐1, cleaved‐caspase‐1, and GSDMD‐N. Electron microscopy revealed FLS pyroptosis after exposure in hypoxia. Next, corresponding shRNAs were transferred into FLS to knock down hypoxia‐inducible factor‐ (HIF‐) 1α, and in turn, NLRP3 and western blot results confirmed the same. The enhanced level of GSDMD was reversed under hypoxia by inhibiting NLRP3 expression. Knockdown and overexpression of GRK2 in FLS revealed GRK2 to be a positive regulator of HIF‐1α. Levels of GRK2 and HIF‐1α were inhibited by eliminating excess reactive oxygen species (ROS). Furthermore, MDP reduced FLS pyroptosis through targeted inhibition of GRK2 phosphorylation. According to these findings, hypoxia induces FLS pyroptosis through the ROS/GRK2/HIF‐1α/NLRP3 pathway, while MDP regulates this pathway to reduce FLS pyroptosis.

G protein-coupled receptor kinase 2 (GRK2) is one of the cytosolic enzymes, and GRK2 translocation induces prostaglandin E2 receptor 4 (EP4) over-desensitization and reduces the level of cyclic adenosine monophosphate (cAMP) to regulate macrophage polarization. However, the role of GRK2 in the pathophysiology of ulcerative colitis (UC) remains unclear. In this study, we investigated the role of GRK2 in macrophage polarization in UC, using biopsies from patients, a GRK2 heterozygous mouse model with dextran sulfate sodium (DSS)-induced colitis, and THP-1 cells. The results showed that a high level of prostaglandin E2 (PGE2) stimulated the receptor EP4 and enhanced the transmembrane activity of GRK2 in colonic lamina propria mononuclear cells (LPMCs), resulting in a down-regulation of membrane EP4 expression. Then, the suppression of cAMP–cyclic AMP responsive element-binding (CREB) signal inhibited M2 polarization in UC. Paroxetine is acknowledged as one of the selective serotonin reuptake inhibitors (SSRI), which is also considered as a potent GRK2 inhibitor with a high selectivity for GRK2. We found that paroxetine could alleviate symptoms of DSS-induced colitis in mice by regulating GPCR signaling to affect macrophage polarization. Taken together, the current results show that GRK2 may act as a novel therapeutic target in UC by regulating macrophage polarization, and paroxetine as a GRK2 inhibitor may have therapeutic effect on mice with DSS-induced colitis.

MYC is an aberrantly regulated transcription factor implicated in approximately 70% of human tumors, where it extensively modulates signaling pathways associated with cancer progression. Inactivating MYC has been shown to inhibit tumor growth and even induce sustained tumor regression across various cancer types, a phenomenon referred to as oncogene addiction. However, in vitro studies reveal that the knockout or knockdown of MYC in numerous tumor cell lines does not necessarily result in cell death, despite these tumors exhibiting MYC addiction in vivo. This discrepancy suggests that the unique tumor microenvironment in vivo may play a critical role in facilitating MYC addiction in cancer cells. MYC is also widely acknowledged for its role in mediating the immune evasion of tumor cells. Nevertheless, due to the extensive regulation of cellular gene expression by MYC and the incomplete understanding of the mechanisms underlying tumor immune escape, the precise pathways through which MYC influences tumor immune evasion remain inadequately elucidated. Recent years have seen the identification of novel tumor immune escape mechanisms, some of which have been demonstrated to be directly or indirectly regulated by MYC. For instance, MYC may contribute to immune evasion by modulating the expression of argininosuccinate synthetase 1 (ASS1), a key enzyme involved in arginine biosynthesis. Herein, in this study, we explore some novel potential mechanisms through which MYC facilitates the immune evasion of tumor cells, alongside a combined therapeutic approach targeting MYC and employing immunotherapy based on this mechanism. Furthermore, we suggest that targeting proteins interacting with MYC to modulate its expression and function may serve as an alternative strategy to direct MYC targeting, thereby expediting the clinical translation of combination therapies.