Aloe Emodin Alleviates Radiation‐Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption

Fan Ouyang; Yaling Li; Haoming Wang; Xiangyang Liu; Xiaoli Tan; Genyuan Xie; Junfa Zeng; Gaofeng Zeng; Qiong Luo; Hong Zhou; Siming Chen; Kai Hou; Jinren Fang; Xia Zhang; Linlin Zhou; Yukun Li; Anbo Gao

doi:10.1002/advs.202406026

journal article·2024-12Open access

Aloe Emodin Alleviates Radiation‐Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption

Fan Ouyang, Yaling Li, Haoming Wang, Xiangyang Liu, Xiaoli Tan, Genyuan Xie, Junfa Zeng, Gaofeng Zeng, Qiong Luo, Hong Zhou, Siming Chen, Kai Hou, Jinren Fang, Xia Zhang, Linlin Zhou, Yukun Li, Anbo Gao

Advanced Science· Volume 11· Issue 47

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Abstract

Abstract Aloe emodin is an anthraquinone of traditional Chinese medicine monomer, which plays a protective action in cardiovascular diseases. However, the regulatory mechanisms of aloe emodin in the protection of radiation‐induced heart damage (RIHD) are unclear. As a novel post‐translational modification, lactylation is considered as a critical mediator in inflammatory cascade and cardiac injury. Here, using a cross of differential omics and 4D label‐free lactylation omics, protein disulfide‐isomerase (P4HB) is identified as a novel target for lactylation, and aloe emodin inhibits the binding of lactate to the K311 site of P4HB. Aloe emodin stabilizes kynurenine metabolism through inhibition of aspartate aminotransferase (GOT2) accumulation on damaged mitochondria. Mechanistically, aloe emodin inhibits phosphorylated glycogen synthase kinase 3B (p‐GSK3B) transcription in the nucleus to repress the interaction of prostaglandin G/H synthase 2 (PTGS2) with SH3 domain of SH3 domain‐containing GRB2‐like protein B1 (SH3GLB1), thereby disrupting the functions of mitochondrial complexes and reducing SH3GLB1‐mediated mitoROS accumulation, eventually suppressing calcium‐binding and coiled‐coil domain‐containing protein 2 (NDP52)‐induced mitophagy. This study unveils the regulatory role of aloe emodin in RIHD alleviation through PTGS2/SH3GLB1/NDP52 axis, indicates aloe emodin stabilizes GOT2‐mediated kynurenine metabolism through P4HB lactylation. Collectively, this study provides novel insights into the regulatory mechanisms underlying the protective role of aloe emodin in cardiac injury, and opens new avenues for therapeutic strategies of aloe emodin in preventing RIHD by regulating lactylation.

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Research context

OpenAlex topics: Sirtuins and Resveratrol in Medicine · Adipose Tissue and Metabolism · Effects of Radiation Exposure

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Cardiovascular Medicine Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou Hunan 412000 P. R. China

Zhuzhou Clinical College Jishou University Jishou Hunan 416000 P. R. China

Department of Critical Care Medicine Hengyang Medical School The Second Affiliated Hospital University of South China Hengyang Hunan 421001 P. R. China

Clinical Research Institute The Second Affiliated Hospital Hengyang Medical School University of South China Hengyang Hunan 421001 P. R. China

Department of Assisted Reproductive Centre Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou Hunan 412000 P. R. China

Clinical Research Center for Arteriosclerotic Disease in Hunan Province Hengyang Hunan 421001 P. R. China

Department of Radiology Hengyang Medical School The First Affiliated Hospital University of South China Hengyang Hunan 421001 P. R. China

Department of Cardiovascular Medicine The Second Affiliated Hospital Hengyang Medical School University of South China Hengyang Hunan 421001 P. R. China

Department of Ultrasound Medicine Hengyang Medical School The Second Affiliated Hospital University of South China Hengyang Hunan 421001 P. R. China

Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer Hengyang Hunan 421001 P. R. China

Funding

National Natural Science Foundation of China · Hunan Provincial Postdoctoral Science Foundation

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