Integration of NSE2 and PKM2 non-canonical signaling activates STAT3 to promote hepatocellular carcinoma progression

Abstract Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, largely due to uncontrolled tumor growth, resistance to apoptosis, and metastatic dissemination. Identifying key regulators that coordinate these malignant phenotypes is essential for improving therapeutic strategies. NSE2, a SUMO E3 ligase component of the SMC5/6 complex, has been implicated in genome maintenance; however, its role in HCC progression and oncogenic signaling remains unclear. Here, we demonstrate that NSE2 is significantly upregulated in HCC tissues and cell lines and that high NSE2 expression correlates with poor clinical outcomes. Transcriptomic profiling following NSE2 silencing revealed enrichment of genes associated with cell cycle progression, metastasis, and survival pathways. Functional assays showed that NSE2 overexpression enhanced HCC cell proliferation, migration, and invasion while suppressing apoptosis, whereas NSE2 knockdown produced the opposite effects both in vitro and in vivo. Mechanistically, we uncover a previously unrecognized non-canonical role of NSE2 in oncogenic signaling. Rather than promoting STAT3 activation through direct SUMOylation of STAT3 or PKM2, NSE2 interacts with STAT3 and facilitates the association between PKM2 and STAT3, thereby enhancing STAT3 Tyr705 phosphorylation without altering total PKM2 expression. PKM2 depletion markedly attenuated NSE2-induced STAT3 Tyr705 phosphorylation, supporting the requirement of PKM2 in this signaling process. Pharmacological inhibition of STAT3 substantially reversed the pro-tumorigenic effects induced by NSE2 overexpression, indicating that STAT3 activation is an important downstream mediator of NSE2-driven HCC progression. Collectively, our findings identify NSE2 as an upstream regulator of the PKM2–STAT3 signaling axis and reveal a non-canonical scaffold/adapter-like mechanism by which NSE2 coordinates oncogenic protein interactions. Targeting the NSE2–PKM2–STAT3 pathway may provide a potential therapeutic strategy for HCC.