m6A-methylated lncRNAs to facilitate keratinocyte pyroptosis and to spark cutaneous toxicities associated with anticancer treatments.

Abstract

e24078 Background: Cutaneous toxicities are common adverse effects (AEs) associated with antineoplastic therapies, including cytotoxic chemotherapies, targeted therapies, and immunotherapies. These AEs require considerable attention due to their psychosocial consequences, negative health outcomes, and financial implications, which may lead to the interruption or discontinuation of systemic antineoplastic treatments. Methods: To explore the mechanism responsible for cutaneous toxicities associated with anticancer treatments, female C57BL/6J mice aged 6-8 weeks were subjected to a 30-day administration of the chemotherapeutic agent Docetaxel and the kinase inhibitor Osimertinib. Subsequently, RNA-seq and MeRIP-seq were performed on skin tissue samples to identify differentially expressed genes and m6A modifications. Results: After a 30-day treatment, significant pathological phenotypes, such as erythema and edema, were prominently observed in the skin tissue of drug-treat groups. RNA-seq analysis indicated a marked up-regulation of pyroptosis-related genes compared to the control group. The administration of Docetaxel and Osimertinib to HaCaT keratinocytes also demonstrated morphological characteristics indicative of pyroptosis. Furthermore, MeRIP-seq analysis revealed significant differences in m6A peaks with lncRNA Malat1. ChIRP assay demonstrated that Malat1 directly interacts with the gene body of Serpinb6b, thereby linking it to the splicing and transcriptional machinery at nuclear speckles and facilitating gene expression. The m6A modification of Malat1 resulted in a diminished interaction with Serpinb6b, leading to a subsequent down-regulation of Serpinb6b expression. This down-regulation of Serpinb6b was associated with an enhanced expression of cathepsin D and L, which subsequently activate Caspase-8 and Caspase-9, culminating in the cleavage of Caspase-3 and finally initiating the pyroptosis process. Conclusions: Docetaxel and Osimertinib have the potential to induce pyroptosis in both HaCaT keratinocytes and murine models by enhancing the m6A modifications of lncRNA Malat1. This finding may offer a novel approach for the development of pharmacological interventions aimed at preventing or treating drug-induced cutaneous toxicities.