Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux

作者全名："Liu, Ruixue; Li, Fengjuan; Hao, Shuai; Hou, Dongyao; Zeng, Xue; Huang, He; Sethi, Gautam; Guo, Jun; Duan, Chenyang"

作者地址："[Liu, Ruixue; Hao, Shuai; Zeng, Xue; Huang, He; Sethi, Gautam; Duan, Chenyang] Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, Chongqing 400010, Peoples R China; [Li, Fengjuan; Guo, Jun] Jinan Univ, Affiliated Hosp 1, Dept Cardiovasc Med, Guangzhou 510660, Peoples R China; [Hao, Shuai] Nanjing Univ, Jinling Hosp, Affiliated Hosp, Res Inst Gen Surg,Med Sch, Nanjing 210002, Peoples R China; [Hou, Dongyao] Hubei Univ Med, Taihe Hosp, Dept Anesthesiol, Shiyan 442000, Peoples R China; [Sethi, Gautam] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore 117600, Singapore; [Sethi, Gautam] Natl Univ Singapore, NUS Ctr Canc Res, Yong Loo Lin Sch Med, Singapore 117600, Singapore; [Guo, Jun] Jinan Univ, Affiliated Hosp 1, Dept Cardiovasc Med, 613 West Rd Huangpu Ave, Guangzhou 510660, Peoples R China; [Duan, Chenyang] Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, 76 Linjiang Rd, Chongqing 400010, Peoples R China"

通信作者："Sethi, G (通讯作者)，Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore 117600, Singapore.; Sethi, G (通讯作者)，Natl Univ Singapore, NUS Ctr Canc Res, Yong Loo Lin Sch Med, Singapore 117600, Singapore.; Guo, J (通讯作者)，Jinan Univ, Affiliated Hosp 1, Dept Cardiovasc Med, 613 West Rd Huangpu Ave, Guangzhou 510660, Peoples R China.; Duan, CY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, 76 Linjiang Rd, Chongqing 400010, Peoples R China."

来源：PHARMACOLOGICAL RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001177080900001

JCR分区：Q1

影响因子：9.1

年份：2024

卷号：200

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Sepsis; Olaparib; Ferroptosis; Mitophagy; Cardiac function

摘要："Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5 mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p < 0.05). The mechanism through which Olaparib ameliorates ferroptosis in cardiac and leukocyte cells post-sepsis is attributed to its facilitation of mitophagy, thus favoring mitochondrial integrity. In conclusion, our findings suggest that low-dose Olaparib can improve mitochondrial quality by accelerating mitophagy flux, consequently inhibiting ferroptosis and preserving cardiac function after sepsis."

基金机构："National Natural Science Foundation of China [82272252, 81900377]; Science and Technology Program of Guangzhou: Key Lab of Guangzhou Basic and Translational Research of Pan-vascular Diseases [202201020042]; Natural Science Foundation of Chongqing [2023NSCQ-MSX0559]; Natural Science Foundation of Guangdong [2022A1515011133]"

基金资助正文："<B>Funding</B> This work was supported by the National Natural Science Foundation of China (Nos. 82272252 and 81900377) , Science and Technology Program of Guangzhou: Key Lab of Guangzhou Basic and Translational Research of Pan-vascular Diseases (202201020042) , the Natural Science Foundation of Chongqing (No. 2023NSCQ-MSX0559) and the Natural Science Foundation of Guangdong (No. 2022A1515011133) ."