Affiliated Hospital of Guangdong Medical University

Systemic lupus erythematosus (SLE) is a prototypical autoimmune connective tissue disease in which the immune system is aberrantly activated, producing various autoantibodies that target the body's tissues, particularly the kidneys. Approximately 50% of patients with lupus nephritis (LN) eventually progress to end-stage renal disease. Despite the availability of multiple therapies, their effectiveness is often limited by individual patient differences. Recent studies have identified a new signaling pathway, the cyclic GMP-AMP synthetase (cGAS)-interferon gene stimulating factor (STING) innate immune pathway. Research has indicated that the serum levels of cGAS, STING, and type I interferon are significantly higher in mice with SLE or LN compared with normal populations. Experimental findings also suggest that the absence of cGAS and STING significantly reduces autoantibody production and alleviates tissue inflammation in autoimmune mouse models. These observations highlight the potential of targeting this pathway as a treatment for patients with SLE and LN. However, significant translational hurdles remain, including contradictory evidence from murine models, a complete lack of human trial data for leading candidates, and the inherent risk of viral reactivation owing to systemic immunosuppression. This article provides an overview of the cGAS-STING pathway, discusses its relevance to SLE and LN, and summarizes over 20 inhibitors targeting cGAS/STING. Furthermore, we emphasize the key clinical challenges and prospects of targeted drugs in this pathway.

This study investigated the molecular mechanisms underlying the inhibitory effects of hexavalent chromium (Cr(Ⅵ)) exposure on testosterone synthesis in bovine testicular Leydig cells. First, bovine Leydig cells were isolated and purified, cultured after purity identification, and the effect of different dose gradients of Cr(Ⅵ) on cell viability after 12 h of exposure was detected using the CCK-8 method. Cell proliferation was assessed using a cell proliferation assay kit. Testosterone levels were measured by ELISA. Intracellular reactive oxygen species (ROS) levels were detected using the DCFH-DA fluorescent probe. Cell autophagy was examined by the monodansylcadaverine (MDC) method. Changes in mitochondrial membrane potential were determined using the JC-1 probe. Ultrastructural changes in mitochondria were observed via transmission electron microscopy. The expression of key genes involved in testosterone synthesis, cell autophagy, mitochondrial fusion, mitochondrial fission, and mitophagy was detected by qRT-PCR. Differentially expressed genes were screened through RNA-seq. Our results demonstrate that Cr(Ⅵ) treatment significantly suppressed testosterone synthesis. Concurrently, Cr(Ⅵ) enhanced intracellular MDC levels and induced mitochondrial dysfunction, characterized by ultrastructural damage, reduced mitochondrial membrane potential, and disrupted mitochondrial dynamics. RNA sequencing analysis revealed that Cr(Ⅵ) activates BNIP3 recruitment and high expression within cells. Subsequent BNIP3 silencing using siRNA interference significantly attenuated Cr(Ⅵ)-induced abnormalities in the expression of mitochondrial genes and intracellular ROS accumulation. Moreover, BNIP3 expression knockdown markedly upregulated the mRNA expression of key steroidogenic genes and the level of testosterone in cell supernatant. These findings suggest that Cr(Ⅵ) inhibits testosterone synthesis in Leydig cells through BNIP3-mediated mitochondrial damage. This study identifies BNIP3 as a potential therapeutic target and provides a theoretical foundation for addressing Cr(Ⅵ)-associated male reproductive dysfunction.

Hepatitis B virus (HBV) infection drives macrophages toward an M2-polarized phenotype, contributing to immune evasion and viral persistence. However, the underlying mechanisms involving post-translational modifications and metabolic reprogramming remain poorly understood. This study integrates multi-omics and functional analyses to characterize lysine acetylation and lipid metabolic alterations in HBV-induced macrophages. In vitro and in vivo models confirmed HBV-promoted M2 polarization, marked by elevated CD206/CD163 expression and anti-inflammatory cytokine secretion. Acetylomic profiling identified 450 modified proteins and 432 quantifiable sites, with significant upregulation of peptides associated with chromatin remodeling and metabolic regulation. Lipidomic analysis revealed extensive reprogramming, including downregulation of phosphatidylcholines, phosphatidylinositols, and oxidized lipids, and upregulation of specific sphingolipids and triacylglycerols. Functional enrichment linked acetylated proteins to lipid metabolic processes and oxidative stress response. These findings suggest that HBV remodels macrophage acetylation and lipid metabolism, which may contribute to the development of an immunosuppressive microenvironment, providing new insights into potential therapeutic strategies targeting acetylation or lipid pathways in chronic HBV infection. SIGNIFICANCE: This study systematically characterizes lysine acetylation profiles and lipid metabolic reprogramming in HBV-induced macrophages using multi-omics and functional assays. It identifies HBV-driven acetylation changes in 450 proteins, which target chromatin remodeling and metabolic regulation, as well as distinct lipid alterations including reduced lipid storage and modified glycerophospholipids and sphingolipids. The study reveals that crosstalk between acetylation and lipid metabolism fosters an immunosuppressive microenvironment that supports HBV persistence. These findings fill critical gaps in understanding the mechanisms of HBV-induced macrophage polarization and provide novel therapeutic targets for chronic HBV infection.