Objective: Myocardial injury is a fatal adverse effect of adriamycin (ADR), which greatly limits its clinicalapplication. Numerous studies have shown that Huashi Baidu formula (HBF) may exert a satisfactoryeffect on myocardial function repair. This study aims to reveal the underlying mechanisms and mainbioactive compounds (BACs) of HBF against myocardial injury. Methods: Firstly, this study established an ADR-induced mouse model to assess the protective effects ofHBF against myocardial injury. Subsequently, transcriptomic profiling was conducted to screen the differentially expressed genes among the HBF treatment, ADR-induced model, and normal control groups.Following the construction and analysis of protein–protein interactions, gene set enrichment analysis,and co-expression matrix, the key targets of HBF against myocardial injury were screened and further validated based on the ADR-induced mouse model. An integrative approach combining network mapping,molecular docking, and molecular dynamics simulation was performed to identify the representative BACs. Results: Based on an ADR-induced myocardial injury mouse model, HBF significantly ameliorated myocardial injury by improving body weight loss, decreasing mortality, and rescuing severe cardiac fibrosis. A totalof 361 ADR-related genes and 42 HBF therapeutic effect-related genes were identified with the thresholdsP < 0.05 and fold change (FC) > 1.2 or < 0.833. Transcriptomic profiling-based networks demonstrated thatthe nuclear factor erythroid 2-related factor 2 (NRF2)-cyclic AMP-dependent transcription factor ATF-3(ATF3)-sulfiredoxin-1 (SRXN1) axis-mediated ferroptosis was the key target of HBF against myocardialinjury. In vivo validation showed that HBF treatment effectively inhibited serum enzymatic biomarkers ofgeneral myocardial injury (aspartate aminotransferase, lactate dehydrogenase, and creatine kinase), myofi- broblast activity (transforming growth factor beta 1 and a-smooth muscle actin), inflammatory cytokines(tumor necrosis factor-a and interleukin-6), oxidative damage (superoxide dismutase, malondialdehyde,accumulated iron content, and TUNEL-positive cells). Mechanically, HBF may restore the dysregulation ofthe NRF2-ATF3-SRXN1 signal axis, leading to inhibition of ferroptosis-associated protein expression.Emodin, rhein, and lactiflorin were identified as the underlying representative BACs of HBF against myocardial injury due to the strong binding affinities between candidate BACs and key targets [Kelch-like ECHassociated protein 1 (KEAP1), ATF3, SRXN1, system Xc- (SLC3A2/SLC7A11), glutathione peroxidase 4(GPX4), ferroportin (FPN), glutathione synthetase (GSS)]. Molecular dynamics simulations further verifiedthese findings, revealing the stable binding among the three components and the key targets. Conclusion: HBF may attenuate ADR-induced myocardial injury via modulating NRF2-ATF3-SRXN1 axismediated ferroptosis, and emodin, rhein, and lactiflorin are potential representative BACs.
关键词:
阿霉素;铁死亡;GPX4;化湿败毒方剂;心肌损伤;NRF2-ATF3-SRXN1轴;系统Xc
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Project Supported:
This research was funded by the National Key R&D Program of China (Nos. 2023YFC2308200, 2023YFC3502900), National Natural Science Foundation of China (Nos. 82304830, 82405159, 82174084), Fundamental Research Funds for the Central PublicWelfare Research Institutes (Nos. ZZ16-YQ-026, ZXKT23008, ZXKT24003, ZZ16-XRZ-038), and Scientific and Technological Inno vation Project of China Academy of Chinese Medical Sciences (No.CI2023E002).
Weijie Li a, Xiang Li a, Congying Huang a, Yudong Liu a, Zhaochen Ma a, Zhaoyin Zhou b, c, Qiuyan Guo a, Congmin Xia d, Chao Wang a, Yute Zhong a, Ping Wang a, Haiyu Xu a, e,?. Huashi Baidu formula may attenuate adriamycin-induced myocardial injury via modulating NRF2-ATF3-SRXN1 axis-mediated ferroptosis[J]. Chinese Herbal Medicines (CHM),2026,18(3):621-634
