SF3A3 Drives Tumorigenesis in Endometrial Cancer by Enhancing c‐FOS Expression and Represents a Potential Therapeutic Target

Abstract Aberrant alternative splicing plays a crucial role in tumorigenesis. Here, splicing factor 3A subunit 3 (SF3A3) is significantly upregulated in endometrial cancer (EC) tissues and associated with poor prognosis. Functionally, SF3A3 drives tumor progression by promoting cell proliferation, suppressing apoptosis, and enhancing cisplatin resistance in vitro and in vivo. Mechanistically, SF3A3 regulates alternative splicing of fos proto‐oncogene, AP‐1 transcription factor subunit (c‐FOS), an oncogene linked to chemoresistance, resulting in a ≈2‐fold increase in full‐length c‐FOS expression and activation of downstream anti‐apoptotic pathways. Notably, phenylethyl isothiocyanate (PEITC) as a direct inhibitor of SF3A3 through database screening and biophysical validation via surface plasmon resonance and mass spectrometry is identified. PEITC reduces c‐FOS expression and induces apoptosis in EC cells. Moreover, encapsulating PEITC in a hydrogel delivery system significantly enhances its therapeutic efficacy by enabling controlled release, reducing dosing frequency, and improving clinical applicability. The therapeutic potential of SF3A3 inhibition is further validated using patient‐derived tumor‐like cell clusters (PTCs), where PEITC and the c‐FOS inhibitor T‐5224 exhibit synergistic effects in suppressing EC. Collectively, our findings establish SF3A3 as a novel oncogenic regulator in EC and highlight PEITC, particularly in its hydrogel formulation, as a promising therapeutic strategy for improving clinical outcomes in EC patients.