LncRNA432-miR-21-y-DAPK2 ceRNA crosstalk regulates antibacterial response in hypoxia stress through mediating mitochondrial apoptosis in teleost fish

Bing Han; Linxin Zhou; Yaxuan Shi; Feng Zhao; Jie Ji; Kai Zhang; Shaowu Yin; Xianhui Ning

doi:10.1016/j.ijbiomac.2025.139694

LncRNA432-miR-21-y-DAPK2 ceRNA crosstalk regulates antibacterial response in hypoxia stress through mediating mitochondrial apoptosis in teleost fish

Int J Biol Macromol. 2025 Jan 9:139694. doi: 10.1016/j.ijbiomac.2025.139694. Online ahead of print.

Authors

Bing Han¹, Linxin Zhou¹, Yaxuan Shi¹, Feng Zhao¹, Jie Ji², Kai Zhang², Shaowu Yin³, Xianhui Ning⁴

Affiliations

¹ Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Jiangsu Key Laboratory of Ocean-Land Environmental Change and Ecological Construction, School of Marine Science and Engineering, Nanjing Normal University, Nanjing 210023, Jiangsu, China.
² Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Jiangsu Key Laboratory of Ocean-Land Environmental Change and Ecological Construction, School of Marine Science and Engineering, Nanjing Normal University, Nanjing 210023, Jiangsu, China; Co-Innovation Center for Marine Bio-Industry Technology of Jiangsu Province, Lianyungang 222005, China.
³ Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Jiangsu Key Laboratory of Ocean-Land Environmental Change and Ecological Construction, School of Marine Science and Engineering, Nanjing Normal University, Nanjing 210023, Jiangsu, China; Co-Innovation Center for Marine Bio-Industry Technology of Jiangsu Province, Lianyungang 222005, China. Electronic address: [email protected].
⁴ Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Jiangsu Key Laboratory of Ocean-Land Environmental Change and Ecological Construction, School of Marine Science and Engineering, Nanjing Normal University, Nanjing 210023, Jiangsu, China; Co-Innovation Center for Marine Bio-Industry Technology of Jiangsu Province, Lianyungang 222005, China. Electronic address: [email protected].

PMID: 39798738
DOI: 10.1016/j.ijbiomac.2025.139694

Abstract

As cold-blooded vertebrates, fish are sensitive to environmental changes. The outcome of pathogen infections in fish therefore is highly shaped by hypoxia. The epigenetic regulation of competitive endogenous RNA (ceRNA) bridging non-coding RNAs and mRNAs represents a promising mechanism modulating antibacterial response plus environmental stress. Here, we for the first time systematically analyzed the ceRNA crosstalk in fish response to the combined stimulation of hypoxia and bacterial infection (HB) dual-stimulation. We found that mitochondrial apoptosis initiated by loss of mitochondrial membrane potential was the main causative for liver damage induced by HB challenge in fish. Accordingly, through whole transcriptome analysis, an apoptosis-associated ceRNA network was constructed, based on which a key crosstalk consisting of lnc432, miR-21-y and DAPK2 was identified. Mechanistically, DAPK2 acted as a positive regulator, knockdown of which significantly increased the bacterial burden during hypoxia by promoting mitochondrial apoptosis. MiR-21-y inhibited DAPK2 expression at both mRNA and protein levels by interacting with its 3'UTR, thereby enhancing DAPK2-mediated apoptosis determinations, and exacerbating bacterial infection during hypoxia. Lnc432 knockdown significantly increased miR-21-y and decreased DAPK2, and substantially promoted the expression of genes associated with mitochondrial apoptosis and enhanced the bacterial load during hypoxia stress. Finally, we revealed that lnc432 sponged miR-21-y to alleviate its suppression on DAPK2 in the ceRNA regulatory way. Our findings reveal that lnc432-miR-21-y-DAPK2 ceRNA crosstalk occurs in fish response to bacterial infection during hypoxic stress through mediating mitochondrial apoptosis. This study provides novel insights into the mechanism underlying the interactions among pathogens, hosts and environmental factors.

Keywords: Antibacterial response; DAPK2; Hypoxia; LncRNA; MiR-21-y; Mitochondrial apoptosis.