ILF3 promotes proliferation and invasion of hepatocellular carcinoma cells through STAT3 phosphorylation and formation of an endogenous complex with SRPK1.

Interleukin enhancer-binding factor 3 (ILF3/NF90) is a multifunctional nuclear factor implicated in diverse malignancies, yet whether ILF3 engages functionally relevant protein-protein interactions within hepatocellular carcinoma (HCC) signaling networks remains incompletely defined. Here, we show that ILF3 is upregulated in HCC across public cohorts and local tissue specimens and that higher ILF3 abundance is associated with adverse clinical features. ILF3 depletion suppresses HCC cell proliferation, migration, invasion, and xenograft growth. Unbiased immunoprecipitation-mass spectrometry identifies serine/arginine-rich protein-specific kinase 1 (SRPK1) as an endogenous interaction partner of ILF3. ILF3 knockdown reduces SRPK1 abundance by accelerating SRPK1 mRNA decay, whereas SRPK1 reconstitution restores STAT3 phosphorylation and substantially rescues the impaired malignant phenotypes. Conversely, SRPK1 knockdown phenocopies ILF3 depletion and reduces p-STAT3 (Tyr705) without materially altering total STAT3. RNA-seq and qPCR validation show coordinated disruption of JAK-STAT-related transcriptional programs after ILF3 loss, and tissue immunohistochemistry supports reduced ILF3, SRPK1, p-STAT3 (Tyr705), Bcl-2, and Ki67 in ILF3-depleted xenografts. These findings establish a functional ILF3-SRPK1-STAT3 relationship in HCC and indicate that ILF3 supports malignant progression partly by maintaining SRPK1 abundance and STAT3 signaling competence.