METTL14 integrates tumor-derived SAM to drive parabrachial epigenetic rewiring in pancreatic cancer.

Tumor-neural crosstalk drives cancer progression and neurological symptoms, yet how tumors rewire brain circuits remains unclear. Here, we identified upregulated methyltransferase-like 14 (METTL14) in lateral parabrachial nucleus glutamatergic neurons (LPBNGlu) as a key regulator of pain-depression comorbidity in pancreatic ductal adenocarcinoma (PDAC) mice. METTL14 inhibition reversed PDAC-induced neuronal hyperexcitability and alleviated behavioral deficits. Mechanistically, METTL14 coordinated the tumor-derived S-adenosylmethionine (SAM) to promote N6-methyladenosine (m6A) modification of adrenomedullin (ADM) mRNA, enhancing neuronal hyperactivation and potentiating LPBNGlu projections to the paraventricular thalamus (PVT) and lateral hypothalamus (LH). ADM suppression and chemogenetic or optogenetic silencing of LPBNGlu → PVTGlu/LHGlu circuits significantly mitigated comorbidity. Moreover, elevated circulating SAM in PDAC patients and mice amplifies this pathway. A methionine-restricted diet (MRD) reduced SAM levels, mitigating comorbidity and suppressing tumor growth. Our findings unveil the SAM-METTL14-ADM axis and LPBNGlu → PVTGlu/LHGlu neurocircuits in PDAC-induced brain remodeling, positioning MRD as a promising therapeutic strategy to improve patient outcomes.