MRPL42 Knockdown Suppresses the Malignant Functions of Hepatocellular Carcinoma by Regulating Oxidative Phosphorylation

Abstract

Objective

The diagnosis and treatment of hepatocellular carcinoma (HCC) remain unsatisfactory, underscoring the urgent need to explore new regulatory factors. This study aimed to uncover the regulatory role of mitochondrial ribosomal protein L42 (MRPL42) in HCC development and assess its clinical potential as a therapeutic target and prognostic biomarker.

Methods

MRPL42 expression in HCC was analyzed in datasets obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. MRPL42 expression was detected via reverse transcription quantitative polymerase chain reaction and immunohistochemistry, and its diagnostic and prognostic abilities were assessed via receiver operating characteristic (ROC) curves and Kaplan–Meier curves. Cell proliferation was assessed via the Cell Counting Kit-8 assay, migration via the wound healing assay, and invasion via Transwell experiments. The molecular mechanisms underlying MRPL42 knockdown-mediated suppression of HCC progression were analyzed via transcriptome sequencing. Western blot analysis was used to measure protein levels. The ATP content and mitochondrial respiratory chain complex I activity were determined via commercial reagent kits.

Results

MRPL42 overexpression predicted HCC occurrence and poor prognosis. MRPL42 knockdown suppressed the malignant functions of HCC. Transcriptomic analysis revealed that differentially expressed genes after MRPL42 knockdown were closely linked to oxidative phosphorylation (OXPHOS). MRPL42 knockdown inhibited the protein expression of the mitochondrial activity markers PGC-1α and MT-ND1 and reduced ATP content and mitochondrial respiratory chain complex I activity, indicating that MRPL42 deficiency impaired mitochondrial OXPHOS. Furthermore, MRPL42 knockdown suppressed the malignant functions of HCC cells by regulating OXPHOS.

Conclusion

MRPL42 is overexpressed in HCC and is a potential biomarker for HCC diagnosis and prognosis. In regulating OXPHOS, MRPL42 knockdown suppressed HCC malignant function, highlighting its potential as a therapeutic target.

Keywords

Hepatocellular carcinoma (HCC) / Mitochondrial respiratory chain / Metabolic reprogramming / Biomarker / MRPL42

References

[1] Bray F, Laversanne M, Sung Het al. . Global cancer statistics 2022: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin.. 2024, 74(3): 229-263

[2] Brown ZJ, Tsilimigras DI, Ruff SMet al. . Management of hepatocellular carcinoma: A review. JAMA Surg.. 2023, 158(4): 410-420.

[3] Toh MR, Wong EYT, Wong SHet al. . Global epidemiology and genetics of hepatocellular carcinoma. Gastroenterology.. 2023, 164(5): 766-782.

[4] Wang W, Wei C. Advances in the early diagnosis of hepatocellular carcinoma. Genes Dis.. 2020, 7(3): 308-319.

[5] Pang BY, Leng Y, Wang Xet al. . A meta-analysis and of clinical values of 11 blood biomarkers, such as afp, dcp, and gp73 for diagnosis of hepatocellular carcinoma. Ann Med.. 2023, 55(1): 42-61.

[6] Hu S, Liu Y, Yang Qet al. . Liquid biopsy using cell-free DNA in the early diagnosis of hepatocellular carcinoma. Invest New Drugs.. 2023, 41(3): 532-538.

[7] Li JJ, Lv Y, Ji H. Diagnostic performance of circulating tumor DNA as a minimally invasive biomarker for hepatocellular carcinoma: A systematic review and meta-analysis. PeerJ.. 2022, 10. e14303

[8] Shaik MR, Sagar PR, Shaik NAet al. . Liquid biopsy in hepatocellular carcinoma: The significance of circulating tumor cells in diagnosis, prognosis, and treatment monitoring. Int J Mol Sci.. 2023, 24(13): 10644.

[9] Cauchy F, Fuks D, Belghiti J. HCC: Current surgical treatment concepts. Langenbecks Arch Surg.. 2012, 3975681-695.

[10] Chang Y, Jeong SW, Young Jang Jet al. . Recent updates of transarterial chemoembolilzation in hepatocellular carcinoma. Int J Mol Sci.. 2020, 21(21): 8165.

[11] Raoul JL, Forner A, Bolondi Let al. . Updated use of tace for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence. Cancer Treat Rev.. 2019, 72: 28-36.

[12] Llovet JM, De Baere T, Kulik Let al. . Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol.. 2021, 185293-313.

[13] Chen J, Sun S, Li Het al. . Il-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via stat3/cd155 signaling axis. Front Immunol.. 2024, 15: 1373321.

[14] Zhao Y, Zhang YN, Wang KTet al. . Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anticancer therapy. Biochim Biophys Acta Rev Cancer.. 2020, 1874(1. 188391

[15] Rimini M, Rimassa L, Ueshima Ket al. . Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in nonviral unresectable hepatocellular carcinoma: An international propensity score matching analysis. ESMO Open.. 2022, 76. 100591

[16] Fujiwara N, Friedman SL, Goossens Net al. . Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol.. 2018, 683): 526-549.

[17] Zhou Y, Zhao H, Ren Ret al. . Gpat3 is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. Theranostics.. 2024, 1493470-3485.

[18] Roth KG, Mambetsariev I, Kulkarni Pet al. . The mitochondrion as an emerging therapeutic target in cancer. Trends Mol Med.. 2020, 26(1): 119-134.

[19] Pecoraro A, Pagano M, Russo Get al. . Ribosome biogenesis and cancer: Overview on ribosomal proteins. Int J Mol Sci.. 2021, 22(11): 5496.

[20] Jiang W, Zhang C, Kang Yet al. . Mrpl42 is activated by yy1 to promote lung adenocarcinoma progression. J Cancer.. 2021, 1282403-2411.

[21] Hao C, Duan H, Li H, et al. Knockdown of mrpl42 suppresses glioma cell proliferation by inducing cell cycle arrest and apoptosis. Biosci Rep. 2018;38(2):BSR20171456.

[22] Lv J, Gan FY, Li MHet al. . Silencing ncapd3 inhibits tumor growth and metastasis in hepatocellular carcinoma by suppressing pi3k-akt signaling pathway. Curr Med Sci.. 2025, 45(2): 253-263.

[23] Sung H, Ferlay J, Siegel RLet al. . Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin.. 2021, 71(3): 209-249

[24] Nevola R, Ruocco R, Criscuolo Let al. . Predictors of early and late hepatocellular carcinoma recurrence. World J Gastroenterol.. 2023, 29(8): 1243-1260.

[25] Drefs M, Schoenberg MB, Börner Net al. . Changes of long-term survival of resection and liver transplantation in hepatocellular carcinoma throughout the years: A meta-analysis. Eur J Surg Oncol.. 2024, 50(3. 107952

[26] Zhang X, Chang X, Deng Jet al. . Decreased mrpl42 expression exacerbates myocardial ischemia and reperfusion injury by inhibiting mitochondrial translation. Cell Signal.. 2025, 125. 111482

[27] Niu N, Ye J, Hu Zet al. . Regulative roles of metabolic plasticity caused by mitochondrial oxidative phosphorylation and glycolysis on the initiation and progression of tumorigenesis. Int J Mol Sci.. 2023, 248): 7076.

[28] Zhang L, Liu T, Chen Met al. . Dual inhibition of oxidative phosphorylation and glycolysis using a hyaluronic acid nanoparticle nox inhibitor enhanced response to radiotherapy in colorectal cancer. Biomaterials.. 2025, 323. 123437

[29] Zheng J, Wang Q, Chen Jet al. . Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor rorγ represents an effective therapeutic opportunity in osteosarcoma. Cell Rep Med.. 2024, 55. 101519

[30] Pereira-Martins DA, Weinhäuser I, Griessinger Eet al. . High mtdna content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability. Signal Transduct Target Ther.. 2025, 101222.

[31] He Y, Song H, Lv Het al. . Bcap31 promotes colorectal cancer metastasis via oxidative phosphorylation-dependent macrophage immunosuppression: A single-cell transcriptomic study. Free Radical Biol Med.. 2025, 239: 594-606.

[32] Ma J, Mao X, Ren Yet al. . Antagonism of estrogen-related receptor-α inhibits mitochondrial oxidative phosphorylation and reduces m2 macrophage infiltration in endometrial cancer. J Tmmunother Cancer.. 2025, 139. e012521

[33] Keoh LQ, Chiu CF, Ramasamy TS. Metabolic plasticity and cancer stem cell metabolism: Exploring the glycolysis-oxphos switch as a mechanism for resistance and tumorigenesis. Stem Cell Rev Rep.. 2025, 2182446-2468.

[34] Fu H, Zhang J, Chen Het al. . Npr1 promotes lipid droplet lipolysis to enhance mitochondrial oxidative phosphorylation and fuel gastric cancer metastasis. Adv Sci (Weinh).. 2025, 12(37. e03233

[35] Hu DW, Huang CH, He YH, et al. Slc6a14 drives mitochondrial fusion and oxidative phosphorylation to promote cancer stemness and early-onset of breast cancer. Adv Sci (Weinh). 2025,12(45):e10811.

[36] Yu Z, Xu K, Shang Yet al. . Lncrna linc00667 inhibits breast cancer progression by regulating potee to suppress mitochondrial oxidative phosphorylation. Cell Signal.. 2025, 135. 112074

[37] Matsuda E, Hasebe S, Matsuzaka Tet al. . Inhibition of elovl6 activity impairs mitochondrial respiratory function and inhibits tumor progression in fgfr3-mutated bladder cancer cells. Biochim Biophys Acta Mol Basis Dis.. 2025, 18718. 168023

[38] Zhang Y, Lao W, Yang Ket al. . Suv39h1 is a novel biomarker targeting oxidative phosphorylation in hepatitis b virus-associated hepatocellular carcinoma. BMC Cancer.. 2023, 231): 1159.

[39] Liu L, Chen J, Ye Fet al. . Prognostic value of oxidative phosphorylation-related genes in hepatocellular carcinoma. Discov Oncol.. 2024, 151258.

[40] Zhang Y, Li W, Bian Yet al. . Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma. PeerJ.. 2023, 11. e14797

[41] Liang H, Ward WF. Pgc-1alpha: A key regulator of energy metabolism. Adv Physiol Educ.. 2006, 304145-151.

Funding

Guangxi Key Research and Development Program(no. AB22080064)

Guangxi Nanning Qingxiu District Key Research and Development Program of Science and Technology Plan(no. 2020050)

Guangxi Medical and Health Appropriate Technology Development, Promotion and Application Project(no. S2021097)

Guangxi Natural Science Foundation(No. 2017GXNSFAA198126，No.2014GXNSFAA118238)

the Foundation of Scientiffc Research and Technology Development Project of Guangxi Province, China (GuiKeGong1355005-3-5)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology