Lactic acid was formerly regarded as a byproduct of metabolism. However, extensive investigations into the intricacies of cancer development have revealed its significant contributions to tumor growth, migration, and invasion. Post-translational modifications involving lactate have been widely observed in histone and non-histone proteins, and these modifications play a crucial role in regulating gene expression by covalently attaching lactoyl groups to lysine residues in proteins. This discovery has greatly enhanced our comprehension of lactic acid’s involvement in disease pathogenesis. In this article, we provide a comprehensive review of the intricate relationship between lactate and tumor immunity, the occurrence of lactylation in malignant tumors, and the exploitation of targeted lactate-lactylation in tumor immunotherapy. Additionally, we discuss future research directions, aiming to offer novel insights that could inform the investigation, diagnosis, and treatment of related diseases.

Incretin receptor agonists (IRAs), primarily composed of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs), work by mimicking the actions of the endogenous incretin hormones in the body. GLP-1RAs have been approved for use as monotherapy and in combination with GIPRAs for the management of type 2 diabetes mellitus (T2DM). In addition to their role in glucose regulation, IRAs have demonstrated various benefits such as cardiovascular protection, obesity management, and regulation of bone turnover. Some studies have suggested that IRAs not only aid in glycemic control but also exhibit anti-atherosclerotic effects. These agents have been shown to modulate lipid abnormalities, reduce blood pressure, and preserve the structural and functional integrity of the endothelium. Furthermore, IRAs have the ability to mitigate inflammation by inhibiting macrophage activation and promoting M2 polarization. Research has also indicated that IRAs can decrease macrophage foam cell formation and prevent vascular smooth muscle cell (VSMC) phenotype switching, which are pivotal in atheromatous plaque formation and stability. This review offers a comprehensive overview of the protective effects of IRAs in atherosclerotic disease, with a focus on their impact on atherogenesis.

Context: Incretin hormones, primarily composed of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted by enteroendocrine cells (EECs) and play crucial roles in maintaining blood glucose homeostasis. Notably, GIP accounts for two-thirds of the entire incretin effect. However, the secretion and function of GIP are impaired in individuals with type 2 diabetes mellitus (T2DM), and the regulatory mechanisms governing GIP secretion remain unclear. Objective: Our study aims to explore the role of an EEC-enriched protein, Secretagogin (SCGN), in the regulation of GIP secretion. Methods: We collected duodenal tissues from both humans and mice to observe the colocalization of SCGN and GIP in EECs. Additionally, we utilized human cohorts and gene-edited mouse models to investigate the effect of SCGN on GIP secretion. Our study included 128 subjects, comprising 64 individuals diagnosed with newly onset diabetes and 64 age- and sex-matched nondiabetic healthy controls. At the animal level, we employed leptin receptor–deficient (db/db) mice and Scgn knockout mice for our investigations. Results: Our findings indicate that SCGN is abundantly expressed in GIP-producing K cells within the intestinal epithelium of both humans and mice. We observed a positive correlation between SCGN and GIP levels in postprandial states among patients with T2DM, db/db mice, and their healthy controls. Notably, Scgn knockout mice exhibited decreased GIP and insulin secretion. However, SCGN deficiency did not affect K-cell number, GIP mRNA expression, or intestinal morphology. Conclusion: Collectively, these findings demonstrate that SCGN is a key regulator of nutrient-induced GIP secretion.

Lipotoxicity is a well-established phenomenon that could exacerbate damage to islet β-cells and play a significant role in the development of type 2 diabetes, the underlying mechanisms of which, however, remain unclear. In lipotoxic conditions, secretagogin (SCGN), an EF-hand calcium-binding protein abundantly expressed in islets, is found to undergo downregulation. In light of this, we aim to explore the role of SCGN in lipotoxicity-induced β-cell injury. Our findings show that exposure to ox-LDL in vitro or long-term high-fat diets (HFD) in vivo decreases SCGN expression and induces pyroptosis in β-cells. Moreover, restoring SCGN partially reverses the pyroptotic cell death under ox-LDL or HFD treatments. We have observed that the downregulation of SCGN facilitates the translocation of ChREBP from the cytosol to the nucleus, thereby promoting TXNIP transcription. The upregulation of TXNIP activates the NLRP3/Caspase-1 pathway, leading to pyroptotic cell death. In summary, our study demonstrates that lipotoxicity leads to the downregulation of SCGN expression in islet β-cells, resulting in ChREBP accumulation in the nucleus and subsequent activation of the NLRP3/Caspase-1 pyroptotic pathway. Thus, administering SCGN could be a potential therapeutic strategy to alleviate β-cell damage induced by lipotoxicity in type 2 diabetes.

Excessive accumulation of cholesterol in β cells initiates endoplasmic reticulum (ER) stress and associated apoptosis. We have reported that excessive uptake of cholesterol by MIN6 cells decreases the expression of secretagogin (SCGN) and then attenuates insulin secretion. Here, we aimed to determine whether cholesterol-induced SCGN decrease is involved in the modulation of ER stress and apoptosis in pancreatic β cells. In this study, MIN6 cells were treated with oxidized low-density lipoprotein (ox-LDL) for 24 h, and then intracellular lipid droplets and cell apoptosis were quantified, and SCGN and ER stress markers were identified by western blot analysis. Furthermore, small interfer RNA (siRNA)-mediated SCGN knockdown and recombinant plasmid-mediated SCGN restoration experiments were performed to confirm the role of SCGN in ER stress and associated cell apoptosis. Finally, the interaction of SCGN with ATF4 was computationally predicted and then validated by a co-immunoprecipitation assay. We found that ox-LDL treatment increased the levels of ER stress markers, such as phosphorylated protein kinase-like endoplasmic reticulum kinase, phosphorylated eukaryotic initiation factor 2 alpha, activating transcription factor 4 (ATF4), and transcription factor CCAAT-enhancer-binding protein homologous protein, and promoted MIN6 cell apoptosis; in addition, the expression of SCGN was downregulated. siRNA-mediated SCGN knockdown exacerbated β-cell ER stress by increasing ATF4 expression. Pretreatment of MIN6 cells with the recombinant SCGN partly antagonized ox-LDL-induced ER stress and apoptosis. Furthermore, a co-immunoprecipitation assay revealed an interaction between SCGN and ATF4 in MIN6 cells. Taken together, these results demonstrated that pancreatic β-cell apoptosis induced by ox-LDL treatment can be attributed, in part, to an SCGN/ATF4-dependent ER stress response.

Lipotoxicity has been shown to induce the loss of functional β-cell mass and lead to type 2 diabetes, but the mechanism remains unknown. In this study, we aim to explore the role of secretagogin (SCGN) in lipotoxicity-induced β-cell injury. Herein, ox-LDL-treated MIN6 cells are assessed for cell viability, cell apoptosis, and the levels of SCGN and autophagy flux-related proteins. Furthermore, autophagic flux is evaluated using LysoTracker Red staining, transmission electron microscopy (TEM) and autophagy double-labeled adenovirus (mRFP-GFP-LC3) assays. Our results indicate that ox-LDL treatment leads to autophagic cell death, as evidenced by decreased cell viability, aggravated cell apoptosis, and the accumulation of the p62 protein. LysoTracker Red staining, TEM and mRFP-GFP-LC3 assays demonstrate that autophagic flux is blocked in ox-LDL-treated MIN6 cells. Intriguingly, SCGN is significantly decreased in MIN6 cells under lipotoxic conditions. Additionally, siRNA-guided SCGN knockdown blocks autophagic flux triggered by rapamycin, while SCGN restoration alleviates autophagic flux retardation and mitigates cell apoptosis. A physical interaction between SCGN and SNAP29 is validated by bioinformatic analysis, coimmunoprecipitation assays and SCGN knockdown tests. SCGN downregulation reduces the interaction of these two proteins. Taken together, our results indicate that ox-LDL treatment induces apoptotic β-cell death by blocking autophagic flux dependent on SCGN downregulation. SCGN administration prevents lipotoxic β-cell injury and may be a potential therapeutic target to promote β-cell expansion in type 2 diabetes.