J Ethnopharmacol. 2026 Jun 5:121972. doi: 10.1016/j.jep.2026.121972. Online ahead of print.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (Huangqi) is widely used in the clinical management of ischemic heart disease and heart failure, where it improves patient outcomes and quality of life. Isomucronulatol-7-O-glucoside (IM-7G) is a key bioactive flavonoid derived from Huangqi, but its precise pharmacological mechanisms remain incompletely understood.
OBJECTIVE: This study aimed to elucidate the mechanisms underlying early cardiac recruitment and adhesion of monocyte/macrophage (Mo/Mφ) subsets following acute myocardial infarction (AMI), and to identify the molecular targets and therapeutic effects of early IM-7G intervention.
METHODS: Single-cell RNA sequencing was performed on cardiac arterial blood from ST-segment elevation myocardial infarction (STEMI) patients and cardiac immune cells from AMI mice to delineate Mo/Mφ transcriptional states. Putative downstream targets of Hif1a were predicted using an in silico "virtual knockout" approach and validated in myeloid-specific Hif1a conditional knockout (cKO) mice. Echocardiography, flow cytometry, and surface plasmon resonance analyses were conducted to evaluate the therapeutic efficacy and underlying mechanisms of IM-7G in AMI model of mice.
RESULTS: AMI induced profound immune remodeling characterized by myeloid immigration, enhanced glycolysis, and upregulation of Hif1a expression in Mo/Mφ populations. In cardiac macrophages, Hif1a-mediated glycolysis was further elevated, and Thbs1 was identified as a key downstream effector. Myeloid-specific Hif1a deletion significantly improved cardiac function and reduced Ly6C+F4/80+THBS1+ Mo/Mφ infiltration into the myocardium, indicating that HIF-1α promotes immune cell adhesion and cardiac recruitment via THBS1. Moreover, IM-7G treatment markedly improved cardiac function, suppressed inflammatory cytokines, and reduced HIF-1α+THBS1+ Mo/Mφ infiltration. Mechanistically, IM-7G directly bound HIF-1α, inhibiting activation of the HIF-1α/THBS1 axis. These effects were absent in Hif1a cKO mice, confirming that the pharmacological action of IM-7G is HIF-1α-dependent.
CONCLUSION: HIF-1α-mediated glycolytic reprogramming regulates Mo/Mφ migration and adhesion via THBS1, establishing a potential "immunometabolic-adhesion" axis in AMI pathology. Targeted intervention with IM-7G effectively attenuates inflammation and improves cardiac function, providing a promising therapeutic strategy for AMI.
PMID:42250831 | DOI:10.1016/j.jep.2026.121972