ERRFI1 Deficiency Facilitates ErbB1 Hyperphosphorylation to Trigger NLRP3 Inflammasome-Mediated Pyroptosis in Arsenic-Induced Thyroid Injury: In Vivo and In Vitro Evidence

Abstract Arsenicals are widespread endocrine-disrupting contaminants in agricultural environments and food supplies. Our prior work has linked arsenic exposure to thyroid cell pyroptosis and consequent tissue injury, yet the underlying molecular mechanism remains unclear. This study interrogated the ERRFI1-ErbB1/ERK axis mediating sodium arsenite (NaAsO2)-induced thyroid injury using in vivo SD rat models and in vitro Nthy-ori 3–1 cells. In rats, NaAsO2 decreased ERRFI1, boosted ErbB1/ERK phosphorylation, and caused thyroid injury and endocrine dysfunction; these adverse effects were partially reversed by the ErbB1 inhibitor erlotinib. In Nthy-ori 3–1 cells, NaAsO2 elicited NLRP3 inflammasome-dependent pyroptosis, repressed ERRFI1, hyperactivated ErbB1/ERK signaling. Pharmacological bidirectional modulation of ErbB1 confirmed its critical role, while ERRFI1 overexpression dampened ErbB1/ERK phosphorylation and mitigated pyroptosis. Collectively, NaAsO2 represses ERRFI1 to hyperactivate ErbB1/ERK, triggering NLRP3 inflammasome-mediated thyroid cell pyroptosis and endocrine dysfunction. These findings define a novel mechanism of arsenic thyrotoxicity and identify the ERRFI1-ErbB1/ERK axis as a promising intervention target.