ArticleFrontiers in oncology2021
CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma.
Article in Frontiers in oncology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 59 citations in OpenAlex.
- Ferroptosis: The dawn of reversing drug resistance in digestive cancers.Genes & diseases · 2026Review
- Development and validation of a novel glioblastoma prognostic model: identifying STOX1 and ZNF248 as ferroptosis-related biomarkers.Cancer cell international · 2025Article
- USP9X-triggered ferroptosis mediates follicular atresia via deubiquitinating Beclin1 in chicken.Journal of animal science and biotechnology · 2025Article
- Review
- The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies.Frontiers in endocrinology · 2025Review
- Article
- CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer.Molecular medicine (Cambridge, Mass.) · 2024Article
- Ferroptosis: insight into the treatment of hepatocellular carcinoma.Cancer cell international · 2024Review
- Ferroptosis: a new promising target for hepatocellular carcinoma therapy.Molecular and cellular biochemistry · 2024Review
- Dexmedetomidine mitigates lidocaine-induced spinal cord injury by repressing ferritinophagy-mediated ferroptosis by increasing CISD2 expression in rat models.Journal of bioenergetics and biomembranes · 2024Article
- Iron-sulfur protein odyssey: exploring their cluster functional versatility and challenging identification.Metallomics : integrated biometal science · 2024Review
- Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies.Signal transduction and targeted therapy · 2024Review
- Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy.Frontiers in immunology · 2024Review
- Potential therapies for HCC involving targeting the ferroptosis pathway.American journal of cancer research · 2024Review
- Emerging roles and therapeutic potentials of ferroptosis: from the perspective of 11 human body organ systems.Molecular and cellular biochemistry · 2023Review
- Ginsenoside Rh4 inhibits inflammation-related hepatocellular carcinoma progression by targeting HDAC4/IL-6/STAT3 signaling.Molecular genetics and genomics : MGG · 2023Article
- Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Review
- Double-edged roles of ferroptosis in endometriosis and endometriosis-related infertility.Cell death discovery · 2023Review
- Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy.Experimental hematology & oncology · 2023Review
- Interaction mechanisms between autophagy and ferroptosis: Potential role in colorectal cancer.World journal of gastrointestinal oncology · 2023Review
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeSorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC.
methodsBioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions.
resultsCISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened.
conclusionInhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.
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