Hexokinase-2 moonlights as a suppressor of STING-mediated innate immunity
Abstract
Metabolic enzymes are increasingly recognized for “moonlighting” functions beyond their primary metabolic roles. While such non-canonical activities are well characterized in cancer biology, their roles in innate immunity remain poorly defined. Here, we show that Hexokinase II (HK2), a rate-limiting enzyme of glycolysis, suppresses STING-mediated innate immune responses independently of its enzymatic activity. Upon STING activation, reactive oxygen species (ROS) trigger the dissociation of HK2 from the mitochondria to the cytosol. Cytosolic HK2 then interacts with STING, impeding its oligomerization and translocation to the Golgi apparatus, thereby dampening downstream immune signaling. Notably, HK-TAT, a peptide that induces HK2 release from the mitochondria, effectively inhibits STING-dependent immune activation and ameliorates disease phenotypes in STING-driven autoimmune mouse models. Our findings highlight the moonlighting role of HK2 as a negative regulator of STING signaling and provide a potential therapeutic approach for treating autoimmune diseases driven by STING dysregulation.
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BibTeX
@article{zhang2026hexokinase2,
title = {{Hexokinase-2 moonlights as a suppressor of STING-mediated innate immunity}},
author = {Chuchu Zhang and Fang-Xu Li and Ming Gao and Jiali Ma and Siyuan Wang and Bikun Xiao and Bo Zhong and Junjie Zhang},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2026.118187},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124726012660},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Hexokinase-2 moonlights as a suppressor of STING-mediated innate immunity
AU - Chuchu Zhang
AU - Fang-Xu Li
AU - Ming Gao
AU - Jiali Ma
AU - Siyuan Wang
AU - Bikun Xiao
AU - Bo Zhong
AU - Junjie Zhang
PY - 2026
DA - 2026/10/30
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118187
UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124726012660
AB - Metabolic enzymes are increasingly recognized for “moonlighting” functions beyond their primary metabolic roles. While such non-canonical activities are well characterized in cancer biology, their roles in innate immunity remain poorly defined. Here, we show that Hexokinase II (HK2), a rate-limiting enzyme of glycolysis, suppresses STING-mediated innate immune responses independently of its enzymatic activity. Upon STING activation, reactive oxygen species (ROS) trigger the dissociation of HK2 from the mitochondria to the cytosol. Cytosolic HK2 then interacts with STING, impeding its oligomerization and translocation to the Golgi apparatus, thereby dampening downstream immune signaling. Notably, HK-TAT, a peptide that induces HK2 release from the mitochondria, effectively inhibits STING-dependent immune activation and ameliorates disease phenotypes in STING-driven autoimmune mouse models. Our findings highlight the moonlighting role of HK2 as a negative regulator of STING signaling and provide a potential therapeutic approach for treating autoimmune diseases driven by STING dysregulation.
SN - 2211-1247
ER -