ALKBH5 (AlkB Homolog 5, RNA Demethylase)

Furthermore, we detail a diagnostic-therapeutic roadmap that integrates liquid biopsy-based m6A biomarker detection with subtype-specific treatment assignment. Targeting the m6A epitranscriptome represents a paradigm shift in oncology; our framework provides the essential strategic approach needed to overcome context-dependency, offering a logical structure for tumor classification, vulnerability prediction, and the translation of epitranscriptomic insights into patient benefit through personalized, biomarker-guided combination therapies.

We developed RMzyme, a platform that consolidates our findings and provides insights into RMPs and their downstream effects. This resource is expected to facilitate biomedical research into the molecular mechanisms of human diseases through the lens of RNA modifications and multiomics data integration.

Our findings indicated that the deficiency of ALKBH5 mediated the enhanced synthesis of the cholesterol metabolite 27HC, which in turn inhibited ferroptosis in HCC cells and the cytotoxicity of CD8+ T cells, leading to Lenvatinib resistance in HCC cells. While the specific role of 27HC was strongly supported, the potential contributions of other CYP27A1-derived metabolites to this phenotype remain a possibility.

Decreased expression of ALKBH5 contributes to elevated spinal m6A methylation and SGK1 expression, promoting morphine tolerance. Targeted overexpression of ALKBH5 mitigates morphine tolerance, most likely through modulation of SGK1-associated immune signalling pathways. These findings suggest that the ALKBH5-m6A-SGK1 axis may participate in the epigenetic modulation of morphine tolerance and provides a promising molecular target for mitigating morphine tolerance.

Taken together, this study leverages LLM-guided discovery to delineate a novel ALKBH5/CHRM3/ZNF281 regulatory axis controlling ferroptotic susceptibility in PCa. Importantly, a synergistic therapeutic strategy was identified by combining RSL3 with AZD5363, providing novel therapeutic targets and directions for PCa treatment.

See also the graphical abstract(Fig. 1).

We developed a novel predictive panel of serum m6A-related genes that could empower CRC screening and early diagnosis. METTL14, ALKBH5, YTHDC2 expression, and SOX2 protein correlate with tumor-related data and are candidates for CRC prognosis.

In this study, elesclomol (ES) or disulfiram (DSF)/Cu was used to induce cuproptosis, and bathocuproine disulfonic acid (BCS) was used to inhibit it. In vivo, the role of the ALKBH5-ATOX1 axis in AML progression has also been confirmed. In Conclusion, The demethylase ALKBH5 downregulates ATOX1 by reducing its m⁶A levels, thereby modulating cuproptosis in AML-a mechanism that offers potential novel insights and therapeutic targets for AML treatment.

Our systematic machine learning analysis demonstrates that m6A regulators can effectively predict CRC prognosis and immunotherapy response. The eight-gene signature provides a practical tool for clinical risk assessment and treatment decision-making.

Together, the evidence supports the SAM-m6A axis as a practical framework to connect nutrient state with RNA fate decisions. It also highlights key gaps for translation, including target engagement, dose-exposure alignment, and causal validation of m6A-dependent phenotypes.

Moreover, we demonstrated that the high-risk factor AC129507.1 in the lncRNA signature was a novel target of the m6A regulatory axis WTAP/YTHDF3/ALKBH5, and depletion of AC129507.1 could markedly induce ferroptosis in GC. Collectively, these findings provide a candidate strategy for risk classification and better clinical management of GC and shed new insight into the underlying mechanism of AC129507.1 in GC development.

Using proteomics and transcriptomic profiles, we identified wild-type IDH1 as a crucial metabolic enzyme upregulated in gemcitabine plus cisplatin chemotherapy (GP)-resistant NPC...The DHODH inhibitor BAY2402234 markedly sensitized NPC cells to chemotherapy. Clinically, a prognostic model based on DDR and ferroptosis signatures effectively predicted disease relapse risk post-chemotherapy in NPC. This study links DDR to ferroptosis defense via the IDH1/α-KG/ALKBH5/DHODH axis, suggesting DHODH inhibition as a promising therapeutic strategy to overcome chemoresistance in tumors harboring wild-type IDH1.