BACKGROUND: Doxorubicin hydrochloride (DOX) is extensively used in the treatment of various tumors. However, its clinical application is limited due to dose-dependent cardiotoxicity. Currently, few effective strategies exist to mitigate or eliminate DOX-induced cardiomyopathy (DIC). Although ferroptosis is implicated in DIC and its inhibition partially alleviates the condition, the direct targets of DOX in the progression of cardiotoxicity remain unclear. This study aimed to discover the direct targets of DOX in ferroptosis-mediated DIC. METHODS: A DOX pulldown assay was performed to identify proteins specifically binding to DOX in murine hearts, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify candidate proteins. A cardiac injury mouse model was established by DOX treatment. Based on this, multiple ferroptosis biomarkers were detected by flow cytometry, quantitative real-time polymerase chain reaction, western blotting, immunochemistry, etc. Besides, specific activator and inhibitor of signaling pathways were applied to illuminate molecular mechanisms. RESULTS: Glutathione S-transferase P1 (GSTP1) was identified as a DOX target. GSTP1 activity was inhibited in DOX-treated cardiomyocytes, while its overexpression significantly alleviated DIC. Moreover, GSTP1 overexpression inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. Mechanistically, GSTP1 overexpression suppressed c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing reactive oxygen species (ROS) production and inhibiting ferroptosis in DIC. CONCLUSIONS This study identifies the DOX/GSTP1/JNK axis as a critical pathway mediating ACSL4-dependent ferroptosis in DIC. GSTP1 is highlighted as a potential key mediator of ferroptosis and a promising therapeutic target for DIC.

Objective To investigate the clinical value of serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the treatment and therapeutic effect evaluation of patients with an exacerbation of chronic obstructive pulmonary disease.Methods The levels of serum sTREM-1,procalcitonin (PCT) and C-reactive protein (CRP) were determined by enzyme-linked immunosorbent assay (ELISA) in 49 exacerbation of chronic obstructive pulmonary disease (COPD) subjects [acute exacerbation of chronic obstructive pulmonary disease (AECOPD) group],49 stable COPD subjects(sCOPD group) after treatment and 49 healthy volunteers as healthy control group.The levels of sTREM-1,PCT and CRP in different groups were compared and the relationship between the level of sTREM-1 in AECOPD and sCOPD groups,and PCT,and CRP was analyzed,respectively.Results The content of sTREM-1,PCT and CRP between different groups had significant difference(P ＜0.05).The level of sTREM-1 in both AECOPD and sCOPD groups was significantly positive correlated with PCT (P ＜ 0.05) and negative correlated with CRP (P ＞ 0.05).Conclusions For guiding the treatment and curative effect evaluation of patients with AECOPD,sTREM-1 has important clinical reference value.