Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination

Abstract

A growing body of evidence indicates that tumor-associated macrophages (TAMs) are crucial contributors to cancer progression, positioning them as an attractive target for therapeutic intervention. In our previous studies, we found that Platycodon grandiflorum exert anti-melanoma effects by influencing TAMs. Platycodin D (PD), a bioactive compound derived from the dried roots of Platycodon grandiflorum, possesses anti-inflammatory, immunomodulatory, and anti-tumor properties. Based on this, we hypothesized that PD could have anti-melanoma potential and set out to investigate its molecular mechanisms in relation to TAMs. Treatment with PD led to a significant reduction in melanoma tumor weight, inhibition of the mTOR pathway, and suppression of M2-polarized macrophages. PD also downregulated M2 macrophage markers, impaired mitochondrial function, reduced ROS production, and diminished the tumor-promoting functions of TAMs. Through network pharmacology and experimental validation, STAT3 was identified as a central target. PD was shown to decrease JAK2 and p-STAT3 levels, promote JAK2 degradation, and enhance its ubiquitination. In Lyz2^cre/cre JAK2^flox/flox mice, which lack JAK2 specifically in bone marrow-derived macrophages (BMDMs) were resistant to PD's effects on M2 polarization, mitochondrial function, and melanoma suppression. In summary, PD inhibits melanoma growth by targeting JAK2, which in turn influences M2 polarization and mitochondrial function. This study underscores the potential of PD in regulating TAMs, providing new insights into its potential use in cancer therapy.