NLRP3 inflammasome regulates doxorubicin-induced cardiotoxicity by modulating the abundance of gut microbiota

Jinsong Yin; Yuyun You; Juncong Mao; Jialong Qi; Xin Zhang; Yunfei Hong

doi:10.1016/j.taap.2025.117455

NLRP3 inflammasome regulates doxorubicin-induced cardiotoxicity by modulating the abundance of gut microbiota

Toxicol Appl Pharmacol. 2025 Jun 30:502:117455. doi: 10.1016/j.taap.2025.117455. Online ahead of print.

Authors

Jinsong Yin¹, Yuyun You², Juncong Mao¹, Jialong Qi³, Xin Zhang⁴, Yunfei Hong⁵

Affiliations

¹ Department of Cardiology, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China.
² Department of Medical Imaging, Kunming Municipal Hospital of Traditional Chinese Medicine, Kunming, Yunnan 650051, China.
³ Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China.
⁴ Department of Cardiology, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China. Electronic address: zxs2012_3@live.com.
⁵ Department of Cardiology, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China. Electronic address: hongyf28@aliyun.com.

PMID: 40602439
DOI: 10.1016/j.taap.2025.117455

Abstract

Doxorubicin (DOX) is a widely used anthracycline whose dose-dependent cardiotoxicity limits its clinical efficacy. However, the mechanisms underlying its toxicity, particularly the regulatory network involving the Nod-like receptor protein 3 (NLRP3) inflammasome-gut-heart axis, remain incompletely understood. This study aimed to establish cellular and animal models of doxorubicin-induced cardiotoxicity (DIC) and investigate the role of the inflammasome in DIC-associated alterations in gut microbiota abundance. Rat cardiomyocytes (H9c2 cells) were treated with DOX 1, 10, 25, and 50 μmol/L concentrations to assess dose-dependent cardiotoxicity. In vivo, C57BL/6 J and NLRP3/MLKL/RIPK3 knockout (KO) mice received DOX (5 mg/kg, intravenous, every 2 days for 3 doses, cumulative 15 mg/kg) to establish a DIC model. We measured the physiological and biochemical parameters of mice peripheral blood using an automatic biochemical analyzer. Additionally, we quantified the mRNA expression levels of inflammatory factors using a reverse transcription polymerase chain reaction and observed cardiomyocyte apoptosis. Fecal samples were collected from each group for 16S recombinant DNA sequencing to analyze gut microbiota. DOX-induced H9c2 cell damage and inflammatory factor release activated the NLRP3 inflammasome and upregulated autophagy-associated proteins LC3I/II. NLRP3 KO attenuated DOX-induced cardiac damage, modulated the immune environment in mouse blood, and mitigated DIC. NLRP3 KO lowered the abundance of mucinophilic Akkermansia muciniphila and suppressed the cardiotoxic effects of DOX. The cardiotoxic effects of DOX were mediated via the NLRP3 inflammasome. NLRP3 inflammasome may mediate DIC by regulating the abundance of gut Akkermansia muciniphila.

Keywords: Akkermansia muciniphila; Doxorubicin; Doxorubicin-induced cardiotoxicity; Gut-heart axis; NLRP3.