Cellular immunology · 2026
IGF2BP2 promotes cuproptosis of cardiomyocytes through m6A modification of MAP2K1 in sepsis-induced myocardial injury.
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Chen Ruiyao, Lu Lu, Lin Beibei, Chen Chengjie, Liang Yafeng
Аннотация
BACKGROUND: Sepsis-induced myocardial injury (SIMI) has become an important cause of death in septic patients, and it is a multi-faceted pathophysiological process. The present study aims to understand how insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) regulates cardiomyocyte cuproptosis through an m6A-dependent regulation of mitogen-activated protein kinase kinase 1 (MAP2K1), and advance our knowledge of SIMI.
METHODS: In vivo and in vitro SIMI models were developed through lipopolysaccharide (LPS) administration in mice and AC16 cardiomyocytes, respectively. The functions of IGF2BP2 and MAP2K1 in regulating cuproptosis under septic myocardial injury were explored through loss- and gain-of-function approaches. Furthermore, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) experiments as well as actinomycin D experiments confirmed the regulatory interaction of IGF2BP2 with MAP2K1.
RESULTS: In SIMI models, the IGF2BP2 mRNA and protein expressions were all significantly upregulated, accompanied by myocardial pathological damage and poor cardiac function. Knockdown of IGF2BP2 considerably lessened LPS-induced myocardial injury, lowered copper levels in serum and myocardial tissue, and rectified the changed expression of key cuproptosis-related proteins such as MAP2K1, solute carrier family 31 member 1 (SLC31A1), ferredoxin 1 (FDX1), heat shock protein 70 (HSP70), dihydrolipoamide S-acetyltransferase (DLAT), and lipoyl synthase (LIAS). Mechanistically, IGF2BP2 interacts with MAP2K1 mRNA to improve the mRNA stability and protein expression of MAP2K1 through N6-Methyladenosine (m6A) modification. In addition, overexpression of MAP2K1 abrogated the suppressive effects of IGF2BP2 knockdown on cardiomyocyte cuproptosis.
CONCLUSION: IGF2BP2 improves MAP2K1 expression stability via m6A modification, which promotes cardiomyocyte cuproptosis and worsens SIMI. This mechanism might give some possible therapy targets for curing septic myocardium injury.
METHODS: In vivo and in vitro SIMI models were developed through lipopolysaccharide (LPS) administration in mice and AC16 cardiomyocytes, respectively. The functions of IGF2BP2 and MAP2K1 in regulating cuproptosis under septic myocardial injury were explored through loss- and gain-of-function approaches. Furthermore, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) experiments as well as actinomycin D experiments confirmed the regulatory interaction of IGF2BP2 with MAP2K1.
RESULTS: In SIMI models, the IGF2BP2 mRNA and protein expressions were all significantly upregulated, accompanied by myocardial pathological damage and poor cardiac function. Knockdown of IGF2BP2 considerably lessened LPS-induced myocardial injury, lowered copper levels in serum and myocardial tissue, and rectified the changed expression of key cuproptosis-related proteins such as MAP2K1, solute carrier family 31 member 1 (SLC31A1), ferredoxin 1 (FDX1), heat shock protein 70 (HSP70), dihydrolipoamide S-acetyltransferase (DLAT), and lipoyl synthase (LIAS). Mechanistically, IGF2BP2 interacts with MAP2K1 mRNA to improve the mRNA stability and protein expression of MAP2K1 through N6-Methyladenosine (m6A) modification. In addition, overexpression of MAP2K1 abrogated the suppressive effects of IGF2BP2 knockdown on cardiomyocyte cuproptosis.
CONCLUSION: IGF2BP2 improves MAP2K1 expression stability via m6A modification, which promotes cardiomyocyte cuproptosis and worsens SIMI. This mechanism might give some possible therapy targets for curing septic myocardium injury.