HGD-derived N-formylkynurenine promotes small cell lung cancer chemoresistance by activating ATL2-mediated endoplasmic reticulum remodelling.

Tumour cells often express molecules that drive aberrant metabolism and exhibit distinct metabolic patterns to adapt to chemotherapeutic stress, leading to therapeutic resistance. Here, we report that homogentisate 1,2-dioxygenase (HGD) drives the accumulation of N-formylkynurenine (FK) to promote chemotherapy resistance in small cell lung cancer (SCLC) cells. Transcriptomic and metabolomic analyses of patient, mouse and tumour cell samples revealed that HGD expression and tryptophan metabolism are preferentially and coordinately altered in chemotherapy-resistant SCLC cells. Under chemotherapeutic stress, HGD is highly expressed and performs a “moonlighting” function, bypassing the canonical machinery to oxidize tryptophan to FK. HGD-generated FK directly binds to the ER-shaping protein ATL2 to activate ATL2 oligomerization, triggering a “metabolite–organelle” signalling axis that regulates adaptive ER homeostasis. Genetic blockade of HGD or treatment with a specific HGD inhibitor identified in our screen significantly increased chemotherapeutic efficacy. Therefore, targeting HGD-driven aberrant metabolism represents a unique opportunity to disrupt ER homeostasis and improve chemotherapy outcomes in SCLC patients.