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NLRC4 promotes PANoptosis to overcome sorafenib resistance in hepatocellular carcinoma by competitively binding to BCLAF1 with TRIB3

ABSTRACT: Objective: Hepatocellular carcinoma (HCC) is a leading global cause of cancer death with poor prognosis. Sorafenib is the therapeutic agent for HCC, but its clinical efficacy is severely compromised by drug resistance. PANoptosis has been reported to be associated with sorafenib-induced cell death. However, the role of the PANoptosis-related gene NLRC4 in sorafenib-resistant HCC remains unclear. This study aimed to investigate the regulatory role of NLRC4 in PANoptosis in sorafenib-resistant HCC and the underlying mechanisms. Methods: We assessed the role of NLRC4 in regulating PANoptosis in sorafenib-resistant HCC cells using overexpression and knockdown experiments. Then, we performed mass spectrometry and multi-omics to explore the downstream mechanisms of NLRC4 in regulating PANoptosis. Results: These results demonstrate that NLRC4 inhibits cell proliferation and promotes PANoptosis to overcome sorafenib resistance in HCC cells. Further mechanistic studies revealed that NLRC4 interacts with BCLAF1, compromising BCLAF1 stability, thereby strengthening PANoptosis. Transcriptomics and proteomics revealed that TRIB3 is a downstream target of NLRC4, and NLRC4 reduces TRIB3 expression. TRIB3 has been reported to form a complex with BCLAF1. Based on these results, we hypothesized and demonstrated that NLRC4 competitively binds to TRIB3 and modulates BCLAF1 stability to regulate PANoptosis and sensitivity to sorafenib in HCC cells. Conclusion: NLRC4 suppresses HCC sorafenib resistance by promoting PANoptosis though competitively bind to BCLAF1 with TRIB3. These findings suggest the regulatory role of NLRC4 in PANoptosis and offer a potential therapeutic strategy for overcoming sorafenib-resistant HCC.

ORGANISM(S): Homo Sapiens

SUBMITTER: Zhongjun Wu

PROVIDER: PXD078170 | iProX | Fri May 08 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Project description:Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, where sorafenib, a multiple target ty-rosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of the treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying to sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) da-tabase was utilised through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide met-abolic pathways, energy production pathways and other pathways related to cancer aggressive-ness, migration, proliferation, and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified po-tential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression, and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

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NLRC4 promotes PANoptosis to overcome sorafenib resistance in hepatocellular carcinoma by competitively binding to BCLAF1 with TRIB3

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