Oncogenic GPR161 Drives Melanoma Proliferation and Metabolic Activity through TXNIP Inhibition

Melanoma progression is driven by both oncogenic signaling and metabolic reprogramming; however, the roles of G-protein-coupled receptors (GPCRs) in these processes remain unclear. Here, we identified GPR161 as an oncogenic GPCR that is significantly upregulated in melanoma and associated with poor survival in advanced-stage melanoma. Functional studies revealed that GPR161 promotes melanoma cell proliferation and migration, whereas its suppression attenuates these malignant phenotypes. Using promoter analysis and chromatin immunoprecipitation-quantitative polymerase chain reaction, we demonstrated that signal transducer and activator of transcription 3 (STAT3) binds directly to and transcriptionally activates GPR161. Inhibition or silencing of STAT3 reduced GPR161 expression and impaired melanoma cell growth. Transcriptomic profiling further identified thioredoxin-interacting protein (TXNIP) as a key downstream target negatively regulated by GPR161. GPR161 depletion increased TXNIP expression, leading to reduced glycolytic capacity and proliferation under both physiological and high-glucose conditions. STAT3 knockdown recapitulated these effects by establishing a STAT3-GPR161-TXNIP regulatory axis. Analysis of the cancer genome atlas datasets confirmed an inverse correlation between GPR161 and TXNIP expression and showed that low TXNIP levels predicted poor overall survival. Together, our findings revealed that GPR161 promotes melanoma malignancy by linking STAT3 activation to TXNIP suppression and metabolic enhancement. This study identified GPR161 as a potential biomarker and therapeutic target in melanoma.