NEK7 couples SDHB to orchestrate respiratory chain electron transport homeostasis that impedes liver fibrosis PMID: 41315267

ADC Targets in Oncology

2026-04-10

NEK7 couples SDHB to orchestrate respiratory chain electron transport homeostasis that impedes liver fibrosis

Nat Commun. 2025 Nov 28;16(1):10751. doi: 10.1038/s41467-025-65790-0.

Zhenzhen Sun ^# ¹ ² ³ ⁴ , Le Sun ^# ¹ ³ ⁴ , Hu Hua ¹ ³ ⁴ , Ying Ren ¹ ³ ⁴ , Wenping Zhu ¹ ³ ⁴ , Xu Wang ² , Wei Gu ² , Songming Huang ¹ ³ ⁴ , Dandan Zhong ¹ ⁵ , Ying Sun ⁶ ⁷ , Yue Zhang ⁸ ⁹ ¹⁰ , Aihua Zhang ¹¹ ¹² ¹³ ¹⁴ , Zhanjun Jia ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China.
2. Department of Endocrinology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, China.
3. Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China.
4. Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, P. R. of China.
5. Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China.
6. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China. [email protected].
7. Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China. [email protected].
8. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China. [email protected].
9. Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China. [email protected].
10. Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, P. R. of China. [email protected].
11. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China. [email protected].
12. Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China. [email protected].
13. Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, P. R. of China. [email protected].
14. State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
15. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China. [email protected].
16. Department of Endocrinology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, China. [email protected].
17. Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, P. R. of China. [email protected].
18. Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, P. R. of China. [email protected].
19. Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China. [email protected].
# Contributed equally.

Abstract

The mode of electron transport in mitochondrial respiratory chain determines whether it generates energy or more Reactive Oxygen Species (ROS), a key for cellular adaptation to diverse oxygen environments. However, the understanding of the mechanisms remains incomplete. Here, we find that NIMA-related kinase 7 (NEK7), targeted to mitochondria by its signal peptides, binds to Succinate Dehydrogenase complex iron sulfur subunit B (SDHB), stabilizing the spatial conformation of complex II and promoting forward electron transport. Deficiency of NEK7 in hepatocytes induces reverse electron transport (RET) and inhibits mitochondrial respiration, thereby promoting ROS generation, triggering spontaneous liver fibrosis and aggravating CCl₄-induced liver fibrosis, which can be attenuated by RET inhibitors. More importantly, NEK7 overexpression effectively alleviates CCl₄- and choline-deficient, high-fat diet-induced liver fibrosis. Overall, these findings highlight the pivotal role of NEK7 in orchestrating complex II and electron transport, providing new insights into the regulation of mitochondrial homeostasis and potential fibrosis treatments.