Ginsenoside Rb1 alleviates AS co-depression disease by targeting the LPCAT3 and modulating the ACSL4/LPCAT3/ALOX15...

Atherosclerosis (AS) and depression are major global health burdens with high comorbidity, yet effective treatments are limited. While ginsenoside Rb1 (GRb1) has shown promise in alleviating both conditions individually and in comorbidity, its precise mechanisms of action remain unclear.

This study investigated whether GRb1 alleviates AS co-depression by targeting LPCAT3 and modulating the ACSL4/LPCAT3/ALOX15 ferroptosis pathway.

In vivo, an AS co-depression model was established in ApoE^-/- mice through a combination of high-fat diet feeding and restraint stress. Following intragastric administration of GRb1, adeno-associated virus (AAV)-mediated knockdown of LPCAT3 was employed to validate its target. The anti-atherosclerotic efficacy was assessed by measuring serum lipid profiles, plasma inflammatory cytokines, and evaluating pathological tissue sections. Antidepressant-like effects were evaluated through behavioral tests. Western blotting, molecular docking, and transmission electron microscopy (TEM) were utilized to investigate the anti-ferroptotic effects and associated molecular signaling pathways. In vitro, primary mouse hippocampal neurons were stimulated with lipopolysaccharide (LPS) to mimic in vivo stress. Lentivirus-mediated LPCAT3 knockdown combined with GRb1 treatment was applied, allowing for parallel evaluation of pharmacological efficacy and validation of the underlying mechanisms.

GRb1 ameliorated AS co-depression in vivo, downregulating the expression of ACSL4, LPCAT3, and ALOX15 proteins, while promoting the expression of SLC7A11 and GPX4, thereby enhancing anti-oxidant capacity and inhibiting ferroptosis. Hippocampal LPCAT3 knockdown normalized the expression of the above pathway proteins, alleviated oxidative stress, and suppressed ferroptosis. Additionally, in vitro experiments demonstrated that GRb1 exerted cytoprotective effects, including anti‑apoptotic and anti‑ferroptotic activities. Following LPCAT3 knockdown, the expression of ferroptosis‑related proteins was more effectively restored, anti-oxidant capacity was enhanced, and mitochondrial morphology was improved.

Ferroptosis represents a central mechanism underlying the comorbidity of AS and depression. GRb1 exerts its therapeutic effects by targeting LPCAT3 and modulating the ACSL4/LPCAT3/ALOX15 ferroptosis pathway to attenuate inflammation, oxidative stress, and mitochondrial dysfunction. This study identifies LPCAT3 as a specific target of GRb1 and establishes ferroptosis inhibition as a promising therapeutic strategy for AS co-depression.