Quercetin suppresses the proliferation of thyroid cancer cells by reducing the expression level of DPP4 and inhibiting its enzyme activity.

Thyroid cancer is a prevalent endocrine malignancy with a rising incidence and limited therapeutic options for advanced disease. Cistanches Herba, a traditional medicinal herb, contains bioactive compounds with reported antitumor potential, yet its molecular mechanisms in thyroid cancer remain unclear. Here, an integrated network pharmacology strategy was employed to identify active compounds and therapeutic targets of Cistanches Herba. Active constituents were screened using TCMSP and ETCM databases, and candidate targets were predicted via SwissTargetPrediction and SEA. Thyroid cancer-associated differentially expressed genes were retrieved from GEO and TCGA datasets, and overlapping analysis was performed to identify convergent targets. Molecular docking was applied to evaluate compound-target interactions, followed by experimental validation in thyroid cancer cell lines. Twenty-five active compounds and 739 putative targets were identified, with enrichment analyses highlighting cancer-related signaling pathways. Among the intersecting targets, DPP4 emerged as a key candidate, exhibiting significant overexpression in thyroid cancer and association with poor prognosis. Docking analysis predicted strong binding between DPP4 and quercetin, a major constituent of Cistanches Herba. Consistently, quercetin selectively suppressed thyroid cancer cell proliferation, downregulated DPP4 expression, and inhibited DPP4 enzymatic activity in a dose- and time-dependent manner. Moreover, DPP4 knockdown recapitulated the antiproliferative effects of quercetin. Collectively, these findings identify DPP4 as a functional therapeutic target for thyroid cancer and demonstrate that quercetin inhibits thyroid cancer cell proliferation through a DPP4-dependent mechanism.