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. 2025 May:186:118015.
doi: 10.1016/j.biopha.2025.118015. Epub 2025 Mar 27.

The AhR/P38 MAPK pathway mediates kynurenine-induced cardiomyocyte damage: The dual role of resveratrol in apoptosis and autophagy

Sara Mohiti  1 , Effat Alizadeh  2 , Line S Bisgaard  3 , Mehrangiz Ebrahimi-Mameghani  4 , Christina Christoffersen  5
Affiliations

The AhR/P38 MAPK pathway mediates kynurenine-induced cardiomyocyte damage: The dual role of resveratrol in apoptosis and autophagy

Sara Mohiti et al. Biomed Pharmacother. 2025 May.

Abstract

Chronic kidney disease increases the risk of cardiovascular disease, partly due to uremic toxins, such as Kynurenine (KYN). While KYN contributes to tissue damage, its role in cardiomyocyte apoptosis and autophagy remains unclear. Resveratrol (RSV) can protect against oxidative stress and inflammation, whereas its specific effects on KYN-induced cardiomyopathy are less understood. This study aimed to investigate the role of KYN in cardiomyocyte apoptosis and autophagy and examine the protective effects of RSV against KYN-induced damage. H9C2 cardiomyocytes were cultured and treated with KYN in presence or absence of RSV or inhibitors of the AhR/Src/MAPKs pathway. Cell viability, apoptosis, mitochondrial membrane potential, and autophagy were assessed using MTT, TUNEL, JC-1, and autophagy detection assays. KYN induced apoptosis, and autophagy in H9C2 cells. RSV pretreatment reduced apoptosis but enhanced autophagy in KYN-treated cells. Inhibiting autophagy or blocking apoptosis, increased KYN-induced apoptosis and autophagy, respectively. Additionally, KYN treatment enhanced AhR activation and the phosphorylation of Src and MAPKs proteins, whereas RSV pretreatment decreased AhR activation and ERK phosphorylation. Inhibitors of p38 MAPK and JNK reduced expression of apoptotic proteins. AhR inhibition also reduced the phosphorylation of p38 MAPK and expression of apoptotic proteins while it enhanced autophagy-related protein expression in KYN treated H9C2 cells. In conclusion, our findings suggest that KYN induces cardiomyocyte apoptosis via the AhR/p38 MAPK pathway whereas RSV can protect against the KYN-induced apoptosis while promoting autophagy. Given the high cardiovascular risk in CKD patients, these findings provide in-sight into potential therapeutic strategies targeting KYN-induced cardiomyopathy.

Keywords: Aryl hydrocarbon receptor; Cardiomyocytes; H9C2; Kynurenine; MAPKs; Tryptophan.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Mehrangiz Ebrahimi-Mameghani reports financial support was provided by Tabriz University of Medical Sciences. Christina Christoffersen reports financial support was provided by Augustinus Foundation. Christina Christoffersen reports financial support was provided by Novo Nordisk Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

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