Aberrant CircTMEM45A Facilitates Inflammatory Progression of Esophageal Squamous Cell Carcinoma through m5C-Mediated NLRP3 Activation

Abstract The lack of diagnostic and therapeutic targets precludes effective treatment of esophageal cancer, rooted in the limited mechanistic understanding of cancer initiation and progression. Nonmutational epigenetic reprogramming, including altered 5-methylcytosine (m5C) modification and circular RNA (circRNA) expression, can drive tumorigenesis and impact cancer biology. Herein, we identified upregulation of the circRNA hsa_circ_0066658 (termed as circTMEM45A) in esophageal squamous cell carcinoma (ESCC) tissues, which was correlated with advanced clinical stages and poor survival. Functionally, elevated circTMEM45A facilitated ESCC malignant progression both in vitro and in vivo. Mechanistically, circTMEM45A interacted with the methyltransferase NSUN2 and m5C readers ALYREF and YBX1, promoting the nuclear export and stability of NLRP3 mRNA to activate the NLRP3/caspase-1/IL1β inflammatory pathway. Additionally, circTMEM45A stabilized IL1B mRNA by binding to U2AF2 and stabilized IL1R1 mRNA by serving as a protein scaffold to enhance the ELAVL1(HUR) interaction, further activating the IL1β/IL1R1 proinflammatory cascade in the tumor microenvironment. These findings reveal cross-talk between circRNA and m5C modification that drives inflammatory progression, highlighting circTMEM45A as a potential diagnostic and therapeutic target in ESCC. Significance: CircTMEM45A induces epigenomic reprogramming to support esophageal cancer development by modulating m5C modifications that converge to activate NLRP3/caspase-1/IL1β inflammatory signaling, indicating circTMEM45A could be targeted to improve detection and treatment strategies.