Cellular signalling · 2025
MiR-383-3p attenuates sepsis-induced myocardial ferroptosis by targeting ATF4 and inhibiting the ATF4-CHOP-CHAC1 signaling axis.
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Li Yazhou, Shao Yan, Su Jie, Dong Shimin
Аннотация
OBJECTIVE: To investigate the role and mechanism of miR-383-3p in sepsis-induced myocardial dysfunction (SIMD), with a focus on ferroptosis.
METHODS: Plasma miR-383-3p levels were measured in sepsis patients with/without SIMD and healthy controls. In vitro, LPS-treated rat cardiomyocytes (H9C2) were transfected with miR-383-3p mimics or inhibitors. Ferroptosis was modulated using erastin or ferrostatin-1. Target prediction and dual-luciferase assays identified ATF4 as a miR-383-3p target. Key markers were assessed by qRT-PCR, Western blot, ELISA, and flow cytometry. In vivo, a murine sepsis model received miR-383-3p agomir; cardiac function and ferroptosis markers were evaluated.
RESULTS: Plasma miR-383-3p was significantly downregulated in SIMD patients, correlating negatively with injury markers (cTnI, CK-MB) and disease severity (SOFA, APACHE II), and positively with cardiac function (LVEF, LVFS). LPS downregulated miR-383-3p and induced ferroptosis/injury in H9C2 cells, which miR-383-3p overexpression mitigated. miR-383-3p directly targeted ATF4 mRNA, suppressing the ATF4-CHOP-CHAC1 axis, reducing lipid peroxidation (lower Fe2+, ROS, MDA,LDH; higher GSH), and downregulating pro-ferroptotic genes (ACSL4). Furthermore, overexpression of ATF4 abolished the protective effects of miR-383-3p, while knockdown of ATF4 phenocopied the suppressive effects of miR-383-3p on the CHOP-CHAC1 axis and ferroptosis. In vivo, miR-383-3p agomir improved cardiac function, reduced inflammation/injury markers, attenuated mitochondrial damage, and inhibited the ATF4-CHOP-CHAC1 pathway in LPS-treated mice.
CONCLUSION: This study identifies a novel mechanism whereby miR-383-3p attenuates SIMD by targeting ATF4 and inhibiting the ATF4-CHOP-CHAC1 signaling axis, thereby suppressing cardiomyocyte ferroptosis. Therefore, our study demonstrates for the first time that the downregulation of miR-383-3p exacerbates SIMD by activating the ATF4-CHOP-CHAC1-mediated ferroptosis pathway.Our findings represents a potential therapeutic target for sepsis-induced cardiac injury.
METHODS: Plasma miR-383-3p levels were measured in sepsis patients with/without SIMD and healthy controls. In vitro, LPS-treated rat cardiomyocytes (H9C2) were transfected with miR-383-3p mimics or inhibitors. Ferroptosis was modulated using erastin or ferrostatin-1. Target prediction and dual-luciferase assays identified ATF4 as a miR-383-3p target. Key markers were assessed by qRT-PCR, Western blot, ELISA, and flow cytometry. In vivo, a murine sepsis model received miR-383-3p agomir; cardiac function and ferroptosis markers were evaluated.
RESULTS: Plasma miR-383-3p was significantly downregulated in SIMD patients, correlating negatively with injury markers (cTnI, CK-MB) and disease severity (SOFA, APACHE II), and positively with cardiac function (LVEF, LVFS). LPS downregulated miR-383-3p and induced ferroptosis/injury in H9C2 cells, which miR-383-3p overexpression mitigated. miR-383-3p directly targeted ATF4 mRNA, suppressing the ATF4-CHOP-CHAC1 axis, reducing lipid peroxidation (lower Fe2+, ROS, MDA,LDH; higher GSH), and downregulating pro-ferroptotic genes (ACSL4). Furthermore, overexpression of ATF4 abolished the protective effects of miR-383-3p, while knockdown of ATF4 phenocopied the suppressive effects of miR-383-3p on the CHOP-CHAC1 axis and ferroptosis. In vivo, miR-383-3p agomir improved cardiac function, reduced inflammation/injury markers, attenuated mitochondrial damage, and inhibited the ATF4-CHOP-CHAC1 pathway in LPS-treated mice.
CONCLUSION: This study identifies a novel mechanism whereby miR-383-3p attenuates SIMD by targeting ATF4 and inhibiting the ATF4-CHOP-CHAC1 signaling axis, thereby suppressing cardiomyocyte ferroptosis. Therefore, our study demonstrates for the first time that the downregulation of miR-383-3p exacerbates SIMD by activating the ATF4-CHOP-CHAC1-mediated ferroptosis pathway.Our findings represents a potential therapeutic target for sepsis-induced cardiac injury.