miR-690 ameliorates hepatic steatosis by targeting NF-KappaB P65 and regulating 15-LOX to induce autophagy in db/db mice

Wenjia Guo; Haifeng Huang; Hong Wang; Xiaodan Tan; Yujun Tu; Chao Gu; Pu Xiang; Lin Chen; Zhe Peng; Yang Yang; Dongzhi Ran; Yin Luo; Junqing Yang

doi:10.1016/j.bcp.2025.117072

miR-690 ameliorates hepatic steatosis by targeting NF-KappaB P65 and regulating 15-LOX to induce autophagy in db/db mice

Biochem Pharmacol. 2025 Jun 25:117072. doi: 10.1016/j.bcp.2025.117072. Online ahead of print.

Authors

Wenjia Guo¹, Haifeng Huang², Hong Wang², Xiaodan Tan², Yujun Tu², Chao Gu², Pu Xiang³, Lin Chen⁴, Zhe Peng⁴, Yang Yang⁴, Dongzhi Ran², Yin Luo², Junqing Yang⁵

Affiliations

¹ Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Department of Pharmacy, Chongqing Health Center for Women and Children, Chongqing 401147, China; Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China.
² Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China.
³ Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China; Department of Pharmacy, Dianjiang People's Hospital of Chongqing, Chongqing 408399, China.
⁴ Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Department of Pharmacy, Chongqing Health Center for Women and Children, Chongqing 401147, China.
⁵ Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Department of Pharmacy, Chongqing Health Center for Women and Children, Chongqing 401147, China; Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China. Electronic address: cqyangjq@cqmu.edu.cn.

PMID: 40578570
DOI: 10.1016/j.bcp.2025.117072

Abstract

The objective of this study was to explore the effects and underlying mechanisms of miR-690 on hepatic steatosis in db/db mice. Our findings revealed that miR-690 was downregulated in the liver of db/db mice and high-glucose (HG)-treated NCTC1469 cells. In vivo, miR-690 overexpression alleviated hyperglycemia, hyperlipidemia, and hyperinsulinemia, improved liver function, and mitigated steatosis and pathological damage. In vitro, miR-690 enhanced cell viability and glucose uptake while reducing lipid deposition. Mechanistically, bioinformatics analysis identified 15-LOX and NF-KappaB P65 as potential miR-690 targets, with their expression levels inversely correlated with miR-690. Furthermore, treatment with miR-690 agomir downregulated 15-LOX and NF-KappaB P65, although dual-luciferase reporter assays confirmed that 15-LOX is indirectly targeted by miR-690. Additionally, miR-690 agomir increased LC3BII/I and Beclin1 levels while decreased P62 and p-mTOR (Ser2448)/mTOR and induced autophagosome formation. Moreover, overexpression of 15-LOX or NF-KappaB P65 reversed the protective effects of miR-690 on autophagy. Collectively, these results suggest that miR-690 exerts hepatoprotective effects against diabetic hepatic steatosis by activating autophagy via modulating 15-LOX and NF-KappaB P65, providing experimental evidence for its potential use in the treatment of hepatic steatosis in diabetes, and new insight into diabetes drug development for targeting miR-690.

Keywords: 15-LOX; Autophagy; Diabetic liver injury; NF-KappaB P65; miR-690.