Guanxinkang Decoction and Its Key Component Isotanshinone II Ameliorate Atherosclerosis Through Modulation of STAT3/ CD36 Signaling and Macrophage Efferocytosis: An Integrated Network Pharmacology and Experimental Validation Study.

INTRODUCTION To investigate the potential anti-atherosclerotic mechanisms of Guanxinkang (GXK), with emphasis on its association with STAT3/CD36 pathway regulation and efferocytosis-related signaling.

Methods

Network pharmacology identified key targets, which were validated by molecular docking and dynamics simulations. ApoE-/- mice and ox-LDL-induced foam cell models established in RAW264.7 macrophages were employed. GXK was administered at 7.22 and 14.43 g/kg/day in vivo and 0.5 and 2 mg/mL in vitro. In vivo and in vitro experiments assessed lipid profiles, plaque formation, inflammatory cytokines, and macrophage efferocytosis.

Results

GXK at both low (7.22 g/kg, GXK-L) and high doses (14.43 g/kg with higher concentration, GXK-H) significantly improved serum lipid profiles (reduced TC, TG, LDL-C; increased HDL-C; P<0.05), reduced atherosclerotic plaque area, and suppressed pro-inflammatory cytokines IL-1β and IL-6 while upregulating IL-10 (P<0.05). Mechanistically, GXK significantly inhibited CD36 expression and reduced STAT3 phosphorylation (P<0.01) and modulated efferocytosis- related proteins TIM-4 (upregulated) and CD47 (downregulated) (P<0.05), suggesting enhanced macrophage efferocytosis capacity. Isotanshinone II, a key GXK component, exhibited similar effects in vitro, alleviating lipid accumulation and modulating CD36, STAT3, and efferocytosis-related proteins.

Discussion

These results suggest that the therapeutic efficacy of GXK in atherosclerosis is attributed to its multi-target regulatory capacity. By suppressing the STAT3/CD36 axis, GXK not only restricts lipid influx but also restores the homeostatic clearance of apoptotic cells through enhanced efferocytosis.

Conclusions

GXK may exert anti-atherosclerotic effects that are associated with modulation of the STAT3/CD36 axis and efferocytosis-related signaling; however, causal validation requires further investigation.