Thioredoxin-interacting protein in radiation-induced pyroptosis and autophagy: Unveiling mechanisms and implications for preventing radiation-induced lung injury.

Radiation-induced lung injury is a serious complication of thoracic radiotherapy, wherein the inflammatory cell death process of pyroptosis and the catabolic process of autophagy are concurrently activated, yet the master regulator coordinating their crosstalk remains unknown. This study identified thioredoxin-interacting protein (TXNIP) as this key regulator. We discovered that TXNIP, upregulated by radiation, does not independently promote pyroptosis and autophagy but directly couples them by competitively binding to NLRP3. This competition displaces Beclin-1 from NLRP3, simultaneously facilitating NLRP3 inflammasome activation (driving pyroptosis) and releasing Beclin-1 to initiate autophagy. The resulting autophagic flux subsequently clears active inflammasomes, forming a self-limiting loop. Thus, TXNIP functions as a critical molecular switch balancing pyroptosis and autophagy. Our findings unveil a novel mechanistic link between these pathways and posit TXNIP as a promising therapeutic target for mitigating RILI.