ECT2 antagonizes lipoic acid to modulate papillary thyroid carcinoma progression through energy metabolism pathways

ECT2 exhibits context-dependent oncogenic or tumor-suppressive roles across multiple cancer types, with its functional output determined by cell-intrinsic factors and extrinsic microenvironmental cues. Nevertheless, the expression dynamics, clinical relevance, and mechanistic underpinnings of ECT2 in papillary thyroid carcinoma (PTC) remain poorly defined. To investigate the role of ECT2 in PTC progression and apoptosis, we analyzed ECT2 expression levels in PTC cell lines and surgical specimens from PTC patients using immunohistochemistry, quantitative real-time PCR (qRT-PCR), and Western blot analysis. The biological functions of ECT2 were assessed via CCK-8, colony formation, transwell migration, and invasion assays through loss-of-function experiments conducted in TPC-1 and BCPAP cells. Furthermore, RNA sequencing was employed to uncover the mechanisms underlying ECT2’s effects on PTC cells. The elevated expression level of ECT2 is closely related to the poor prognosis of patients with thyroid cancer. Moreover, the results of this study show that the expression of ECT2 is significantly upregulated in PTC cells compared with normal epithelial cells. In vitro experiments demonstrated that knockdown of ECT2 significantly inhibited the proliferation ability of PTC cells, while activation of the ECT2 signaling pathway promoted cell proliferation. The ECT2-mediated pro-proliferative effect depends on the activation of the PI3K/AKT pathway and the inhibition of the Lipoic acid (LA) pathway. Additionally, ECT2 may promote the expression of glycolysis-related genes by inducing RhoA phosphorylation and thereby activating the transcription factor MYC. At the same time, it inhibits drug uptake and enhances drug efflux by down-regulating drug influx transporters and up-regulating efflux transporters, thereby increasing the IC50 value of tumor cells to drugs. This study demonstrates that ECT2 acts as a predictive biomarker for PTC and drives PTC cell proliferation through dual regulatory mechanisms: suppression of the LA pathway and activation of the PI3K/AKT signaling pathway. Moreover, ECT2 promotes the expression of glycolysis-related genes by inducing RhoA phosphorylation, which leads to the activation of the transcription factor MYC. Concurrently, ECT2 contributes to chemoresistance by down-regulating influx transporters and up-regulating efflux transporters, thereby reducing drug uptake and enhancing drug efflux. These findings provide novel insights into targeting the ECT2 signaling axis for PTC therapy and highlight the need for further mechanistic and translational investigations.