Inhibition of hexokinase 2 undermines cartilage health and accelerates osteoarthritis

作者：Haokun Xu, Xinyi Zhang, Yijie Fu, Genming Liu, Sirui Yuan, Daizhao Deng, Kai Li, Tinghui Xiao, Ying Lin, Ruijun Lai, Song Xu, Xiaochun Bai, Y Zhang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.05.26.728030 · 研究领域：Osteoarthritis Treatment and Mechanisms、Cancer, Hypoxia, and Metabolism、High Altitude and Hypoxia

Abstract Objective Enhanced glycolysis is a metabolic hallmark of chondrocytes in osteoarthritis (OA); however, the roles of the glycolytic rate-limiting enzyme hexokinase 2 (HK2) in cartilage remain poorly understood. Methods Pharmacological approach (3-bromopyruvate (3-BrPA) treatment) and mice model involving HK2 knockout in Col2a1-expressing chondrocytes are utilized to access the impact of HK2 blockage on cartilage ex vivo and in vivo . The in vivo effects of HK2 inhibition on OA progression were evaluated using a destabilization of the medial meniscus (DMM)-induced OA mouse model, through both intra-articular 3-BrPA administration and chondrocyte HK2 deletion. Additionally, we analyzed published single-cell RNA sequencing (scRNA-seq) datasets from human articular cartilage and integrated these with bulk RNA-seq data from HK2-deficient chondrocytes to characterize HK2 expression features across conditions. Results Both pharmacological inhibition and genetic deletion of HK2 impair cartilage formation ex vivo . Bulk RNA-seq analysis and ex vivo studies demonstrated a promoted ossification-like process due to HK2 ablation in chondrocytes. Through pseudotime analysis of published single-cell RNA sequencing (scRNA-seq) datasets from human articular cartilages, we further identified that HK2 is differentially expressed across conditions, with a feature of a relatively high expression level at terminal stages of chondrocyte differentiation in the context of OA. We next confirme...