The interleukin‑6 (IL‑6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a pivotal role in regulating inflammation and tumorigenesis, making it a significant target for therapeutic intervention. Although the rhizome of Curcuma longa (C. longa) has been extensively investigated, the pharmacological potential of its aerial parts, such as the leaves, remains largely unexplored. The present study investigated the inhibitory effects of the ethyl acetate fraction of C. longa leaf extract (CL‑E) on IL‑6‑induced STAT3 activation in Hep3B hepatoma cells in vitro. CL‑E significantly suppressed IL‑6‑stimulated STAT3 transcriptional activity in a dose‑dependent manner (IC50, 33.9±3.7 µg/ml) without compromising cell viability (up to 60 µg/ml). Mechanistically, CL‑E reduced STAT3 phosphorylation at Tyr705 while enhancing STAT3 phosphorylation at Ser727; this opposing pattern suggests an ERK‑mediated rebalancing of STAT3 signaling that attenuates canonical Tyr705‑dependent activation and augments Ser727‑associated modulation. Additionally, CL‑E inhibited STAT3 nuclear translocation and downregulated the mRNA expression of STAT3 target genes, including C‑reactive protein and suppressor of cytokine signaling 3. Mechanistic investigations revealed that CL‑E promoted extracellular signal‑regulated kinase (ERK)1/2 phosphorylation, leading to increased STAT3 Ser727 phosphorylation. Notably, the inhibitory effect of CL‑E on STAT3 Tyr705 phosphorylation was reversed by MEK1/2 (U0126) or PKC inhibitors (bisindolylmaleimide II), indicating that CL‑E modulates STAT3 signaling through an ERK‑mediated mechanism. Collectively, these in vitro findings identify C. longa leaves as an underutilized botanical resource with the potential to regulate IL‑6/STAT3 signaling, warranting in vivo evaluation to establish its efficacy, safety and pharmacokinetics, and to define potential therapeutic utility in IL‑6/STAT3‑driven conditions.
