Mitochondrial ribosomal protein S30 inhibits ferroptosis and promotes tumor progression in hepatocellular carcinoma via suppressing GPX4 ubiquitination.
Aug 2026· International Journal of Biological Macromolecules· Vol 381, pp.
153878
· 0 citations· 41 references
Medicine
TL;DR
It is confirmed that MRPS30 inhibits ferroptosis by upregulating Glutathione Peroxidase 4(GPX4), thereby promoting the malignant progression of HCC and resistance to lenvatinib, and confirmed that ferroptosis is a promising therapeutic strategy for HCC treatment.
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths, with limited therapeutic options. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has emerged as a promising approach for HCC intervention due to its close association with multiple aspects of liver cancer, such as proliferation, metastasis, and drug resistance. In this study, we identified the oncogene mitochondrial ribosomal protein S30 (MRPS30) associated with HCC prognosis through multi-omics analysis. Using HCC cell lines with MRPS30 knockdown/overexpression and xenograft tumor models, we confirmed that MRPS30 inhibits ferroptosis by upregulating Glutathione Peroxidase 4(GPX4), thereby promoting the malignant progression of HCC and resistance to lenvatinib. Mechanistically, MRPS30 specifically interacts with GPX4 and inhibits the lysine 48 (K48)-linked ubiquitination of GPX4 to maintain its protein stability. By stabilizing GPX4, MRPS30 reduces malondialdehyde (MDA) accumulation and maintains glutathione (GSH) homeostasis, thereby inhibiting ferroptosis and ultimately enhancing the malignant behaviors and drug resistance of HCC. In conclusion, we identified MRPS30 as a prognosis-related gene in HCC and revealed its role in regulating HCC proliferation, metastasis, and drug resistance through ferroptosis. Our findings uncover a key driver of ferroptosis resistance mediated by the MRPS30/GPX4 axis and further confirm that ferroptosis is a promising therapeutic strategy for HCC treatment.
The molecular mechanisms underlying lung metastasis of colorectal cancer (CRC) remain largely elusive, and effective therapeutic agents are still lacking. In this study, we identify levistilide A (LeA) as a potential anti-metastatic agent against CRC lung metastasis. We demonstrate that heat shock protein 90α (HSP90α) is markedly upregulated in CRC and promotes lung metastasis by suppressing ferroptosis. Notably, combined treatment with LeA and the ferroptosis inducer RSL3 further alleviates lung metastatic burden in vivo. Mechanistically, we reveal that the E3 ubiquitin ligase ring finger protein 40 (RNF40) suppresses CRC cell proliferation by directly interacting with HSP90α, inducing ubiquitination at lysine 407 and promoting its proteasomal degradation. RNF40-mediated HSP90α downregulation leads to the accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS), thereby inhibiting CRC cell growth. Collectively, our findings provide mechanistic insights into how LeA directly targets HSP90α or facilitates RNF40-HSP90α-mediated degradation of HSP90α to regulate ferroptosis in CRC.
Jia-Ming He, Chang-Shuo Li, Yingqiang Liu et al.· Cell Death Discovery· 0 citations
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, highlighting the urgent need for novel diagnostic and therapeutic targets. In this study, through integrated proteomic profiling, we identify AP4M1 as a potential therapeutic vulnerability for HCC and characterize its upstream regulatory and downstream effector mechanisms. We show that AP4M1 is markedly upregulated in HCC, correlates with unfavorable prognosis, and is functionally involved in driving HCC progression. Mechanistically, the deubiquitinase USP15 stabilizes AP4M1 by removing K11- and K48-linked polyubiquitin chains at lysine 163 (K163). Additionally, MINK1-mediated phosphorylation of AP4M1 at threonine 69 (T69) is critical for its interaction with GPX4. Through upregulating GPX4, AP4M1 reduces intracellular lipid peroxidation, thereby suppressing ferroptosis and facilitating HCC tumorigenesis and progression. Importantly, combined treatment with the USP15 inhibitor USP15-IN-1 and the GPX4 inhibitor RSL3 exhibits potent anti-tumor efficacy in both in vitro and in vivo models, underscoring the therapeutic potential of targeting the AP4M1 axis in HCC. Collectively, this study delineates the USP15/AP4M1/MINK1/GPX4 axis as a previously unrecognized ferroptosis-suppressive pathway that promotes HCC progression, providing a critical theoretical basis for AP4M1-targeted therapeutic strategies in HCC.
Yuan-Hao Peng, K. Kang, Xuanxuan Li et al.· Cancer Letters· 0 citations
Dysregulation of the ubiquitin-proteasome system (UPS) plays a pivotal role in tumor progression. PSMD11, a non-ATPase regulatory subunit of the 26S proteasome, has been implicated as an oncogenic factor in several cancer types; however, its precise biological function and molecular mechanisms in hepatocellular carcinoma (HCC) remain incompletely understood. In this study, we demonstrated that PSMD11 was markedly upregulated in HCC tissues and correlated with poor patient prognosis. Functionally, PSMD11 overexpression promoted HCC cell proliferation, migration, and invasion, whereas its knockdown exerted opposite effects. Mechanistically, we reveal that PSMD11 drives HCC progression by reprogramming lipid metabolism. We identified a novel pathway in which PSMD11 physically interacted with PSMD7 and PSMD14, leading to decreased ubiquitination of the transcription factors SREBP1/2 and PPAR-γ. Notably, PPAR-γ directly bound to the CPT1A promoter to enhance its transcription, thereby promoting fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). In conclusion, our findings uncover a PSMD11–PSMD14–SREBP1/2-PPAR-γ–CPT1A regulatory axis that orchestrates metabolic reprogramming in HCC. Targeting this signaling cascade may represent a promising therapeutic strategy for the precision treatment of HCC, particularly in tumors exhibiting UPS dysregulation.
Zhi-Hong Huang, Can-Xue Zhang, Chi Zhang et al.· Cell Death & Disease· 0 citations
Summary Hepatocellular carcinoma (HCC) has a poor prognosis, necessitating therapeutic targets, while the role of ubiquitin-specific protease 3 (USP3) in HCC remains unclear. This study aimed to elucidate the function of the deubiquitinating enzyme USP3 in HCC. USP3 was found to be highly expressed in HCC tissues and associated with poor prognosis. Functional assays in cells and animal models confirmed that USP3 promotes tumor proliferation, migration, and invasion. Mechanistically, USP3 directly binds to yes1-associated transcriptional regulator (YAP) via its ubiquitin C-terminal hydrolase (UCH) domain interacting with YAP’s WW domain, removing K11/K48-linked polyubiquitin chains to stabilize the YAP protein. The screening results showed that the pan-deubiquitinating enzyme (DUB) inhibitor PR-619 could inhibit USP3 activity to a certain extent and significantly suppress the growth and metastasis of HCC. Notably, YAP overexpression partially reversed this inhibition. In conclusion, USP3 drives HCC progression by deubiquitinating and stabilizing YAP, and PR-619 demonstrates anti-tumor efficacy, establishing USP3 as a potential therapeutic target for HCC.
Yuan-Hao Peng, H. Nie, Xuanxuan Li et al.· iScience· 0 citations
Ubiquitination plays a critical role in hepatocellular carcinoma (HCC) pathogenesis and is closely linked to ferroptosis. This study investigates the function of OTUB1, a deubiquitinase overexpressed in HCC, in regulating autophagy-dependent ferroptosis. Using integrated bioinformatics, biochemical assays, and xenograft models, we demonstrated that OTUB1 is upregulated in HCC and correlates with poor prognosis. Functionally, OTUB1 knockdown suppressed proliferation and induced ferroptosis, whereas its overexpression promoted malignancy. Mechanistically, OTUB1 competitively binds to p62/SQSTM1, thereby suppressing autophagic flux. Crucially, we identified that OTUB1 stabilizes p62 via non-canonical, D88-dependent deubiquitination by specifically removing K48-linked polyubiquitin chains. This stabilization hinders the initiation of autophagy-dependent ferroptosis. Pharmacological inhibition of autophagy abrogated the ferroptosis induced by OTUB1 knockdown. Furthermore, inhibiting OTUB1 sensitized HCC tumors to Lenvatinib, resulting in synergistic anti-tumor efficacy in vivo. Collectively, these findings reveal that OTUB1 drives HCC progression by stabilizing p62 to block autophagy-dependent ferroptosis. Targeting the OTUB1-p62 axis represents a novel therapeutic strategy to overcome drug resistance and improve outcomes in advanced HCC.
Pengcheng Zhao, Yong-Xin Wang, N. Saeidi et al.· Cell Death Discovery· 0 citations
INTRODUCTION
Ferroptosis and autophagy are recently identified forms of non-apoptotic regulated cell death with strong therapeutic implications for hepatocellular carcinoma (HCC). Mitochondrial ribosomal protein L35 (MRPL35), a mitochondria- specific component of mitoribosomes, has been proposed as a potential therapeutic target for liver cancer. The study focused on autophagy-dependent ferroptosis in HCC, with an emphasis on the functional significance of MRPL35.
METHODS
Bioinformatics approaches, RT-qPCR, along with western blotting, were used to determine MRPL35 expression in HCC. CCK-8, scratch, Matrigel, and flow cytometric assays were used to detect cell proliferation, migration, invasion, and apoptosis. JC-1 staining was used to detect mitochondrial function. Assay kits and C11-BODIPY assay were used to detect GSH, GSSG, MDA, ROS, Fe2+, ATP, and lipid ROS levels. MDA staining and western blotting assessed the presence of autophagosomes and autophagy-related proteins. In addition, western blotting was used to detect γ-H2AX, apoptosis-, ferroptosis, and AMPK/mTOR axis-related proteins. The in vivo effects of MRPL35 were confirmed by subcutaneous tumorigenesis assays in nude mice.
RESULTS
MRPL35 showed abnormally high expression in HCC with a low survival rate. MRPL35 downregulation suppressed cell viability and metastasis, promoted cell apoptosis and autophagy, as well as ROS-dependent DNA damage, inhibited tumor growth, and promoted ferroptosis and autophagy in HCC-bearing mice. MRPL35 interference also promoted autophagy-mediated ferroptosis. In addition, MRPL35 modulated the AMPK/mTOR axis, and AMPK inhibitor Compound C or AMPKα interference reversed the effects of MRPL35 interference on autophagy-mediated ferroptosis.
DISCUSSION
The elucidation of MRPL35's role in mediating the AMPK/mTOR axis is consistent with the well-established pro-tumorigenic role of MRPL35 and the significance of the AMPK/mTOR axis in HCC. The newly characterized MRPL35- AMPK/mTOR axis not only proposes MRPL35 as a therapeutic target for HCC but also advances our understanding of its carcinogenic mechanisms.
CONCLUSION
Overall, a novel regulatory mode of autophagy-reliant ferroptosis was established by the MRPL35/AMPK/mTOR axis in HCC.
Yu-Liang Xu, Li-Shuai Xiao, Zhi-Hu Shi et al.· Current Cancer Drug Targets· 0 citations
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