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 explore the effect of posterior column stability and decompression on the treatment of lumbar burst fracture with nerve injury and its effect on vertebral body and neurological function.Methods Fifty-two cases patients of lumbar burst fracture with nerve injury from February 2005 to July 2014 in Affiliated Hospital of Youjiang Medical College For Nationalities were selected as the research objects and divided into retention group(28 cases) and non-retention group(24 cases) according to the choice of operation method.The surgical clinical efficacy,the changes of the vertebral body and nerve function were compared between two groups.Results At 3 months,6 months and 12 months after operation,the fusion rate,sagittal diameter and the height of the injured vertebral body,pre-vertebral body,and intervertebral space were all significantly increased,while the Cobb angle,the pressure area and the sagittal displacement rate were markedly decreased(F of inner grouP=10.492,8.858,7.432,16.311,19.491,10.329,21.587;P<0.05),and the improvement range of Cobb angle,intervertebral space,the pressure area and sagittal displacement rate of retention group were significant better than non-retention group.There was no significant difference on the fusion rate,the volume of bleeding,the incidence of postoperative complications,Denis pain score,the height of injured vertebral body,pre-vertebral body,and sagittal displacement between the two groups(P>0.05).After operation,the ASIA grade gradually improved,neurological function of the retention group recovered at 6 months after surgery,while non-retention group presented this effect at 12 months after surgery,moreover,at 12 months after operation,the proportion of E grade in retention group was 64.29%,higher than that of non-retention group(45.83%,F=12.758,P<0.001).The levels of neuron-specific enolase(NSE),S100B protein and myelin basic protein(MBP) in retention group were significantly lower than those of the non-retention group at 3 months after surgery(P<0.05).The improvement of S100B and MBP in the reservation group at 6 months after surgery were better than those of non-retention group,while at 12 months after surgery,only the improvement of MBP in retention group showed the better effects than non-retention group.Conclusion Posterior column stability and decompression show a high clinical efficacy on the treatment of lumbar burst fracture with nerve injury and it can significantly improve the vertebral body and neurological function.