Journal Article

HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells

Kwon, Munju, Kim, Koanhoi, Baryawno, Ninib, Park, Dongha, Lee, Dongjun, Oh, Sae-Ock, Kim, Byoung Soo, Kim, Jaesung, Son, Yonghae, Yoon, Sik, Kang, Nakyung

2025

Overview

27-Hydroxycholesterol (27OHChol), a cholesterol metabolite, induces inflammatory responses in monocytic cells and promotes their differentiation into mature dendritic cells. Here, we examined whether inhibition of heat shock protein 90 (HSP90) modulates these responses. Treatment with ganetespib, a selective HSP90 inhibitor, significantly reduced chemokine CCL2 expression, lowering monocytic cell migration. It also suppressed matrix metalloproteinase-9 (MMP-9) expression and attenuated the lipopolysaccharide (LPS) response otherwise amplified by 27OHChol. Furthermore, ganetespib decreased mature dendritic cell markers (CD80, CD83, CD88) and restored endocytic activity, indicating a less activated state. These changes suggest that HSP90 regulates 27OHChol-induced pro-inflammatory activation via its client proteins. To explore this mechanism, we examined the phosphorylation status of signaling proteins. 27OHChol enhanced phosphorylation of Akt and its downstream targets, S6 and 4E-BP1 within the Akt/mTORC1 pathway. Ganetespib reduced total and phosphorylated Akt and 4E-BP1, and selectively inhibited S6 phosphorylation without altering total protein level. Collectively, these findings demonstrate that HSP90 inhibition by ganetespib mitigates 27OHChol-driven monocytic cell activation through suppression of the HSP90-Akt/mTORC1 axis. Targeting this pathway may provide a promising therapeutic strategy for metabolic inflammation associated with oxysterols.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Atherosclerosis / Cardiovascular disease / Cell adhesion & migration / Cell Movement - drug effects / Chemokine CCL2 - metabolism / Cholesterol / Dendritic cells / Dendritic Cells - drug effects / Dendritic Cells - metabolism / Development and progression / Heat shock proteins / HSP90 Heat-Shock Proteins - antagonists & inhibitors / HSP90 Heat-Shock Proteins - metabolism / Humans / Hydroxycholesterols - pharmacology / Inflammation / Inflammation - chemically induced / Inflammation - metabolism / Kinases / Lipopolysaccharides - pharmacology / Monocytes - drug effects / Monocytes - metabolism / Phosphorylation / Phosphorylation - drug effects / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Signal Transduction - drug effects / THP-1 Cells / Triazoles - pharmacology