Abstract

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis, largely due to therapeutic resistance and the limited availability of effective targeted therapies. Aloperine (ALO), a natural alkaloid derived fromSophora alopecuroidesL., exhibits anti-cancer properties in various tumor types; however, its therapeutic potential and underlying mechanism in ESCC remain unclear. Here, we report that ALO inhibited ESCC cell proliferation and colony formation in a dose- and time-dependent manner and induced caspase-dependent apoptosis, accompanied by loss of mitochondrial membrane potential and PARP1 cleavage. Mechanistically, ALO significantly suppressed inflammatory pathways, with IL-6 identified as a critical downregulated target. ALO inhibited IL-6 production by targeting the AP-1 transcription factor complex, as evidenced by reduced cFOS expression and suppressed cJUN phosphorylation. Consequently, ALO inhibited downstream IL-6/JAK-STAT3 signaling. Functionally, exogenous IL-6 rescued ALO-induced loss of cell viability. Notably, the combination of ALO with cisplatin exerted synergistic antitumor effects. In a syngeneic mice model, the combination therapy significantly reduced tumor growth and Ki67 expression while inducing apoptosis, as shown by increased TUNEL staining and cleaved caspase-3 expression, and further suppressing the IL-6/STAT3 axis compared with either monotherapy. Together, these findings demonstrate that ALO exerts potent anti-ESCC activity by targeting the AP-1/IL-6/STAT3 signaling axis. The synergistic efficacy of ALO with cisplatin highlights its potential as a promising therapeutic agent to overcome chemoresistance and improve outcomes in ESCC patients.