Cancer Commun (Lond). 2026 Sep 11;46:0048. doi: 10.34133/cancomm.0048. eCollection 2026.

ABSTRACT

Background: Cancer cells frequently acquire adaptive resistance to targeted therapies; however, strategies capable of concurrently overcoming treatment tolerance and reactivating cell death pathways are currently lacking. Here, we investigated the dual role of ferredoxin 1 (FDX1) in modulating both multikinase inhibitor (MKI) sensitivity and cuproptosis susceptibility in hepatocellular carcinoma (HCC), and sought to develop a therapeutic approach for reversing resistance. Methods: HCC models, both in vitro and in vivo, were employed to investigate the role of FDX1 in MKI resistance and cuproptosis evasion. Polysome profiling, SunTag translation reporters, CRISPR-Cas9 mutagenesis, and mass spectrometry were employed to delineate the underlying mechanisms. A codelivery nanoliposome system was engineered and tested in orthotopic HCC models. Results: Prolonged exposure to MKIs led to the down-regulation of FDX1 protein levels, resulting in MKI resistance and cuproptosis tolerance in HCC both in vitro and in vivo. Mechanistically, we found that MKIs inactivated protein kinase B (PKB, also known as AKT)-mechanistic target of rapamycin (mTOR) signaling, thereby suppressing the SET and MYND domain-containing protein 2 (SMYD2)-mediated methylation of YTH domain family protein 1 (YTHDF1) at lysine 515 (K515). Hypomethylated YTHDF1 was degraded via next to BRCA1 gene 1 protein (NBR1)-dependent autophagy, leading to the repression of N6-methyladenosine modification-dependent translation of FDX1 mRNA. FDX1 deficiency drove MKI resistance by reactivating AKT survival signaling while impairing cuproptosis through reduced divalent copper ions (Cu²⁺) to monovalent copper ions (Cu⁺) conversion and the loss of protein lipoylation. Additionally, restoring FDX1 expression through NBR1 knockdown or YTHDF1 overexpression overcame MKI resistance and resensitized HCC cells to cuproptosis. Finally, a nanoliposomal system, super cuproptosis detonator liposome, designed for the codelivery of NBR1 small interfering RNA, a copper ionophore, and sorafenib restored FDX1-dependent cuproptosis and exhibited marked anti-HCC efficacy, suppressing HCC growth in vivo. Conclusions: MKIs suppressed SMYD2-mediated YTHDF1 methylation at K515 via the inactivation of AKT-mTOR signaling. This led to the inhibition of FDX1 translation, resulting in AKT signaling reactivation and protein lipoylation impairment, effects that contributed to both MKI resistance and cuproptosis tolerance in HCC. Overcoming MKI resistance and resensitizing cells to cuproptosis by targeting NBR1-mediated YTHDF1 degradation using a nanoliposomal codelivery system represents a promising strategy for HCC treatment.

PMID:42729649 | PMC:PMC13562797 | DOI:10.34133/cancomm.0048

Phytomedicine. 2026 Aug 26;161:158760. doi: 10.1016/j.phymed.2026.158760. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbors TP53 mutations at high frequency, yet therapeutic strategies that specifically target mutant p53 remain limited.

PURPOSE: This study aimed to identify S100A6, a calcium-binding protein frequently upregulated in TP53-mutant PDAC, as a critical regulator of mutant p53 stability and tumor progression, and to explore potential S100A6-targeting agents for therapeutic intervention.

METHODS: We integrated computer-assisted drug screening with transcriptomics, acetylation omics, and molecular biology techniques to identify Agrimol B (AgrB), a bioactive compound derived from the traditional Chinese herb Agrimonia pilosa Ledeb., as a potential S100A6-targeting agent.

RESULTS: High S100A6 expression was closely associated with poor prognosis in patients with TP53-mutant PDAC, whereas S100A6 depletion markedly suppressed PDAC cell growth and metastatic potential. Mechanistically, AgrB enhanced the interaction between S100A6 and the deacetylase HDAC2, leading to reduced acetylation of mutant p53 at lysine 382. This disruption activated autophagy-dependent cell death and thereby inhibited PDAC progression.

CONCLUSION: Our findings reveal an S100A6-HDAC2-mutant p53 acetylation axis that regulates TP53-mutant pancreatic tumorigenesis, providing mechanistic evidence supporting S100A6 as a therapeutic vulnerability and highlighting AgrB as a promising natural-product-derived candidate for further development against this aggressive malignancy.

PMID:42700714 | DOI:10.1016/j.phymed.2026.158760