Kushenol O Regulates GALNT7/NF-κB axis-Mediated Macrophage M2 Polarization and Efferocytosis in Papillary Thyroid Carcinoma

Background

The incidence of papillary thyroid carcinoma (PTC) is on the rise globally. It is frequently associated with early lymphatic metastasis, and the poor prognosis tends to be poor once metastasis or recurrence occurs, even with current treatment modalities. Kushenol O, a novel extract derived from Sophora flavescens, has shown remarkable anticancer properties. However, its specific role in the treatment of PTC remains to be elucidated.

Purpose

This objective of this study is to examine the effects of kushenol O on the proliferation and invasion capacity of PTC cells, as well as to delve into its potential mechanisms of action.

Methods

Multi-omics was employed to identify the potential therapeutic targets for PTC. Single-cell RNA sequencing (scRNA-seq) investigated how these targets influence the remodeling of the tumor immune microenvironment (TIME). Kushenol O was employed to treat the PTC cell lines, with assessments conducted on its effects regarding cell viability, apoptosis, oxidative stress, and invasiveness. Molecular simulation was used to validate kushenol O's affinity for the therapeutic targets and biological toxicity. The impact of kushenol O was further evaluated using qRT-PCR and EdU assays, while cytotoxicity was measured by the CCK-8.

Results

GALNT7 is a potential new target for the treatment of PTC. It may regulate the macrophage M2 polarization and efferocytosis in the TIME of PTC through regulating the NF-κB axis. Kushenol O inhibits PTC cells proliferation and promotes apoptosis by inhibiting the expression of GALNT7, induces a decrease in SOD levels and an increase in MDA levels by inhibiting mitochondrial function, and promotes the accumulation of ROS, which inhibits G1 phase and promotes early apoptosis.

Conclusions

Kushenol O may inhibit the inflammation–cancer transformation and tumor progression of PTC by inhibiting GALNT7 and thus regulating NF-κB axis. These findings highlight the potential of kushenol O as immunomodulator or therapeutic agent, which may have important clinical implications.