Piceatannol attenuates thoracic aortic aneurysm progression by targeting STK33

BACKGROUND: Thoracic aortic aneurysm (TAA) is a life-threatening vascular condition with limitedpharmacological interventions. This study aimed to identify novel causaldruggable genes and therapeutic candidates for TAA. METHODS: We performed Mendelian randomization (MR) by integrating cis-expression quantitativetrait loci (eQTL) and genome-wide association studies (GWAS) data to identifycausal genes for TAA. Therapeutic candidates were predicted via the DrugSignatures Database (DSigDB) and prioritized using molecular docking. Theclinical relevance of the lead target, STK33, was assessed in human TAA tissuesusing immunohistochemistry (IHC). The therapeutic efficacy of piceatannol wasrigorously validated across three distinct platforms: Angiotensin II(AngII)-stimulated vascular smooth muscle cells (VSMCs), and two complementaryanimal models (BAPN-induced and AngII-infused TAA mice). RESULTS: MR analysis identified 31 druggable genes significantly associated with TAA risk.Integration with DSigDB and molecular docking pinpointed piceatannol as a potentcandidate targeting STK33. IHC staining revealed that STK33 expression wasmarkedly downregulated in human TAA tissues, a trend consistently observed inAngII-stimulated VSMCs and mouse TAA models. In vivo, piceatannol treatmentsignificantly reduced TAA incidence, mortality, and aortic dilation in bothBAPN-induced and AngII-induced mouse models. Mechanistically, piceatannoleffectively restored STK33 protein levels and attenuated the loss of VSMCcontractile markers (MYH11, α-SMA, and CNN1) both in vivo and invitro. These protective effects were largely abolished by STK33 knockdown,confirming a target-specific mechanism. CONCLUSIONS: Piceatannol attenuates TAA progression, potentially through targeting and stabilizing STK33 expression. By utilizing a multi-model validation strategy (two in vivo modelsand an in vitro cell model), our findings highlight the piceatannol-STK33 axisas a promising therapeutic candidate for TAA.