STK38-mediated feedback loop regulation of the hedgehog pathway governing tumor heterogeneity in renal papillary carcinoma

Papillary renal cell carcinoma (pRCC) is characterized by marked intratumoral heterogeneity, which contributes to therapeutic resistance and disease progression. In this study, we identify STK38 as a key regulator of tumor heterogeneity in pRCC, functioning through non-canonical activation of the Hedgehog (Hh) signaling pathway. STK38 interacts with both KIF7 and GSK3β to promote Hh signaling by facilitating KIF7 ciliary localization and reprogramming GSK3β substrate selectivity, leading to GLI1 stabilization and β-catenin suppression. Moreover, GLI1 directly enhances STK38 transcription, establishing a positive feedback loop that reinforces pathway activation. Notably, depletion of STK38 sensitizes tumor cells to a NETosis-like chromatin release process (tNET release), a form of stress-induced nuclear expulsion associated with immune evasion and metastatic potential. Given the potential pro-metastatic consequences of STK38 inhibition, we instead targeted its downstream effector GLI1 using Glabrescione B, which potently suppressed tumor growth and induced apoptosis in both xenograft and patient-derived organoid models, particularly in STK38-high tumors. These findings position STK38 as a critical modulator of pRCC heterogeneity and support GLI1 inhibition as a promising strategy to disrupt oncogenic signaling while minimizing adverse effects.