Hepatic micropeptide modulates mitochondrial RNA processing machinery in hepatocellular carcinoma

Linyu Zhu¹, Fangzhou Liu², Chengyu Shi³, Xinwan Su², Manman Tan², Shaofang Xie⁴, Meng Yu², Sailan Zou⁵, Yinuo Tan⁶, Shanshan Xie⁷, Jian Liu⁸, Qingfeng Yan⁹, Dante Neculai¹⁰, Qiming Sun¹⁰, Wei Liu¹⁰, Yuan Ding¹¹, Xianghui Fu⁵, Jianzhong Shao⁹, Xu Li⁴, Kefeng Ding¹², Ying Yuan¹³, Tianhua Zhou¹⁴, Aifu Lin¹⁵

Affiliations

¹ Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
² MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China.
³ MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Key Laboratory of RNA Science and Engineering, Institute of Biophysics Chinese Academy of Sciences, Beijing 100000, China.
⁴ Key Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, Zhejiang 310000, China.
⁵ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China.
⁶ Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
⁷ Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310000, China.
⁸ Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang 314000, China.
⁹ MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China.
¹⁰ International School of Medicine, International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang 321000, China.
¹¹ Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, China.
¹² Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Colorectal Surgery and Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
¹³ Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Zhejiang Provincial Clinical Research Center for CANCER, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China. Electronic address: yuanying1999@zju.edu.cn.
¹⁴ Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310000, China. Electronic address: tzhou@zju.edu.cn.
¹⁵ Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiashan, Zhejiang 314000, China; Zhejiang Provincial Clinical Research Center for CANCER, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China. Electronic address: linaifu@zju.edu.cn.

PMID: 40513568
DOI: 10.1016/j.molcel.2025.05.027

Hepatic micropeptide modulates mitochondrial RNA processing machinery in hepatocellular carcinoma

Linyu Zhu et al. Mol Cell. 2025.

. 2025 Jun 19;85(12):2303-2319.e7.

doi: 10.1016/j.molcel.2025.05.027. Epub 2025 Jun 12.

Authors

Affiliations

¹ Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
² MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China.
³ MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Key Laboratory of RNA Science and Engineering, Institute of Biophysics Chinese Academy of Sciences, Beijing 100000, China.
⁴ Key Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, Zhejiang 310000, China.
⁵ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China.
⁶ Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
⁷ Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310000, China.
⁸ Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang 314000, China.
⁹ MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China.
¹⁰ International School of Medicine, International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang 321000, China.
¹¹ Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, China.
¹² Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Colorectal Surgery and Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
¹³ Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Zhejiang Provincial Clinical Research Center for CANCER, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China. Electronic address: yuanying1999@zju.edu.cn.
¹⁴ Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310000, China. Electronic address: tzhou@zju.edu.cn.
¹⁵ Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310000, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiashan, Zhejiang 314000, China; Zhejiang Provincial Clinical Research Center for CANCER, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China. Electronic address: linaifu@zju.edu.cn.

PMID: 40513568
DOI: 10.1016/j.molcel.2025.05.027

Abstract

Micropeptides, originating from noncanonical translation, represent novel biomolecules with critical roles in tissue homeostasis and cancer development. However, the proteomic landscape and functional mechanisms of micropeptides in hepatocellular carcinoma (HCC) remain largely elusive. By employing a newly devised ultrafiltration tandem mass spectrometry assay, we identified an abundance of micropeptides in clinical HCC samples. Among them, a long non-coding RNA (lncRNA)-derived micropeptide mitochondrial RNase P inhibitory peptide (MRPIP) attenuated HCC progression by modulating the mitochondrial RNA processing machinery. Mechanistically, energy-stress-induced MRPIP hindered mitochondrial ribonuclease P (mtRNase P) complex assembly by interacting with HSD17B10 at the R25 residue, which disrupted the HSD17B10 tetramerization and the subsequent HSD17B10-TRMT10C subcomplex formation, leading to perturbed post-transcriptional RNA processing, translation, energy production in mitochondria, and suppressed cancer progression. Strikingly, the 20-aa functional peptide generated from MRPIP sequences robustly inhibited HCC progression in vitro and in vivo. Overall, our study uncovered and characterized a class of HCC-associated micropeptides, shedding light on cancer diagnosis and treatment.

Keywords: RNA processing; hepatocellular carcinoma; micropeptide; mitochondria.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Hepatic micropeptide modulates mitochondrial RNA processing machinery in hepatocellular carcinoma

Affiliations

Hepatic micropeptide modulates mitochondrial RNA processing machinery in hepatocellular carcinoma

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances