SUCNR1 (Succinate Receptor 1)

Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice...Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

SDHA deficiency leads to succinate accumulation, which promotes M2 macrophage polarization through the GPR91/STAT3 pathway, thereby facilitating HCC progression. Based on these findings, serum succinate could be a promising diagnostic biomarker for HCC.

Succinate triggers CCL2 release in macrophages via the GPR91/MALT1/NF-κB pathway, thereby exacerbating pulmonary fibrosis. These findings suggest that targeting succinate signaling may represent a novel therapeutic strategy for IPF.

Overall, this study uncovers that tumor-secreted succinate confers CTx resistance in CRC by activating SUCNR1, thereby driving M2 macrophage polarization. These findings offer novel insights into the mechanisms of CRC resistance and identify potential therapeutic targets within the tumor microenvironment, which could potentially lead to the development of more effective treatment strategies for CRC patients.

Recent metabolomic analyses have revealed elevated succinate levels in bone-related diseases, indicating its potential association with these conditions. The objective of this review is to elucidate the impacts of succinate on different bone-related diseases and to discuss potential therapeutic targets and drug molecules based on its mechanisms of action.

Further experiments revealed that the expression of polarization-related markers in M1-type macrophages was significantly suppressed after treatment with the SUCNR1-neutralizing antibody or the PI3K inhibitor LY294002. These findings suggest that succinate may activate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway via SUCNR1 to promote the polarization of NEC macrophages toward the M1 phenotype, thereby accelerating NEC progression.

This process activates the mitochondrial GSH-GPX4 axis, thereby inhibiting mitochondrial ferroptosis. Through these two mechanisms, INHBA ultimately promotes the malignant progression of colorectal cancer.

Further GSEA analysis of risk-model-related genes revealed the significant differences in inflammatory response between high-and low-risk groups. In conclusion, we constructed an inflammation related risk model using internal scRNA data and external bulk RNA data, which can accurately distinguish survival outcomes in AML patients.

Moreover, SUCNR1 inhibitor (NF-56-EJ40) inhibited glycolysis of intestinal epithelial cells (IECs) in the co-culture system with Th17 cells, including downregulation of oxygen consumption rate (OCR) and increased extracellular acidification rate (ECAR) reflecting overall glycolytic flux, and regulated the expression of glycolysis-related proteins, such as GLUT1, HK-II, and LDHA. Collectively, our findings indicate that microbiota consumption of succinate can ameliorate DSS-induced UC through suppressing Th17, reducing IECs glycolysis, lowing the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving dysbiosis.

Finally, overexpression experiments further validated the core regulatory role of SUCNR1 in this process. This study reveals the molecular mechanism by which DMM induces ferroptosis in TNBC cells through the SUCNR1/PI3K/HIF-1α signaling pathway, providing new theoretical insights for the exploration of TNBC pathogenesis and clinical treatment strategies.

These results might indicate that tumors that shifted toward a higher glucose influx and a higher oxidation of succinate via mitochondrial complex II present an ideal environment for radioresistance development. Patients with a high transcriptional expression of both SLC2A3 and SDHA had a significantly higher risk of local recurrence after treatment with RT or CRT.

Controlling succinate by SDH parallel with SUCNR1 signal regulation by NARNPs will be a novel understanding mechanism and candidate for therapeutic target in lung cancer.