Recent studies reveal context-dependent activation mechanisms across tissues, including lysosomal cell death (LCD)-induced K+ efflux in myeloid cells (Gaidt et al., 2017), IRF3-mediated transcriptional regulation in myocardial injury (Li et al., 2019), ER retention and deubiquitination of NLRP3 during HSV-1 infection (Wang et al., 2020), and WDR5/DOT1L-mediated histone methylation, which promotes IRF3 binding to the Nlrp3 promoter in hepatic fibrosis (Xiao et al., 2023). This evidence concerns the gene DOT1L and Hepatic fibrosis.