GATA5 impedes NSCLC progression by activating SDPR and repressing CNR1 expression

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, necessitating the identification of novel molecular mechanisms and therapeutic targets. GATA5, a member of the GATA family of transcription factors, has been implicated as a potential tumor suppressor in various malignancies; however, its role and regulatory mechanisms in NSCLC pathogenesis remain largely unexplored. GATA5 expression and promoter methylation status were assessed in NSCLC cell lines, patient tissues, and public databases using RT-PCR, western blot, methylation-specific PCR, and immunohistochemistry. Functional studies were performed using in vitro assays (proliferation, colony formation, apoptosis, migration, invasion) and in vivo xenograft models. Mechanistic insights were obtained through RNA sequencing, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments. The therapeutic potential of CNR1 inhibition was evaluated using the selective antagonist AM251 alone and in combination with cisplatin. GATA5 was frequently silenced by promoter hypermethylation in NSCLC, and low GATA5 expression correlated with poor patient prognosis. Functionally, GATA5 acted as a potent tumor suppressor, inhibiting proliferation, migration, invasion, and tumor growth while promoting apoptosis. Mechanistically, GATA5 directly bound to the SDPR promoter to activate its transcription, and SDPR was identified as a critical mediator of GATA5’s tumor-suppressive effects. The GATA5-SDPR axis negatively regulated CNR1, an oncogenic effector. Pharmacological inhibition of CNR1 with AM251 reversed the pro-tumorigenic effects of GATA5 loss and synergized with cisplatin to enhance anti-tumor efficacy both in vitro and in vivo. Our findings establish the GATA5-SDPR-CNR1 axis as a critical tumor-suppressive pathway in NSCLC. Targeting CNR1 represents a promising therapeutic strategy to overcome cisplatin resistance and improve outcomes in patients with GATA5-silenced tumors.