PMID- 36577999
OWN - NLM
STAT- MEDLINE
DCOM- 20221230
LR  - 20230103
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 19
IP  - 1
DP  - 2022 Dec 28
TI  - Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases.
PG  - 315
LID - 10.1186/s12974-022-02682-w [doi]
LID - 315
AB  - BACKGROUND: Dysregulated activation of the inflammasome is involved in various 
      human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. 
      Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) 
      have been designed and developed, none of the inhibitors are clinically 
      available. Growing evidence suggests that targeting apoptosis-associated 
      speck-like protein containing a CARD (ASC), the oligomerization of which is the 
      key event for the assembly of inflammasome, may be another promising therapeutic 
      strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an 
      antineoplastic drug, has been evidenced to have anti-inflammation effects. 
      However, its anti-inflammatory mechanism is still largely unknown. METHODS: 
      Middle cerebral artery occlusion (MCAO), experimental autoimmune 
      encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to 
      investigate the therapeutic and anti-inflammasome effects of LND. The inhibition 
      of inflammasome activation and ASC oligomerization by LND was evaluated using 
      western blot (WB), immunofluorescence (IF), quantitative polymerase chain 
      reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone 
      marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed 
      using molecular mock docking, surface plasmon resonance (SPR), and drug affinity 
      responsive target stability (DARTS). RESULTS: Here, we find that LND strongly 
      attenuates the inflammatory injury in experimental models of 
      inflammasome-associated diseases including autoimmune disease-multiple sclerosis 
      (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of 
      inflammasome activation independent of its known targets including hexokinase 2 
      (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC 
      and inhibits its oligomerization. CONCLUSIONS: Taken together, our results 
      identify LND as a broad-spectrum inflammasome inhibitor by directly targeting 
      ASC, providing a novel candidate drug for the treatment of inflammasome-driven 
      diseases in clinic.
CI  - (c) 2022. The Author(s).
FAU - Chen, Chen
AU  - Chen C
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Zhou, YuWei
AU  - Zhou Y
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Ning, XinPeng
AU  - Ning X
AD  - Department of Molecular Biology and Biochemistry, Zhongshan School of Medicine, 
      Sun Yat-sen University, Guangzhou, 510080, China.
FAU - Li, ShengLong
AU  - Li S
AD  - Department of Molecular Biology and Biochemistry, Zhongshan School of Medicine, 
      Sun Yat-sen University, Guangzhou, 510080, China.
FAU - Xue, DongDong
AU  - Xue D
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Wei, CaiLv
AU  - Wei C
AD  - Department of Molecular Biology and Biochemistry, Zhongshan School of Medicine, 
      Sun Yat-sen University, Guangzhou, 510080, China.
FAU - Zhu, Zhu
AU  - Zhu Z
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Sheng, LongXiang
AU  - Sheng L
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Lu, BingZheng
AU  - Lu B
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Li, Yuan
AU  - Li Y
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Ye, XiaoYuan
AU  - Ye X
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, China.
FAU - Fu, YunZhao
AU  - Fu Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, China.
FAU - Bai, Chuan
AU  - Bai C
AD  - Institute of Human Virology, Key Laboratory of Tropical Disease Control of 
      Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Cai, Wei
AU  - Cai W
AD  - Department of Molecular Biology and Biochemistry, Zhongshan School of Medicine, 
      Sun Yat-sen University, Guangzhou, 510080, China.
FAU - Ding, YuXuan
AU  - Ding Y
AD  - Department of Molecular Biology and Biochemistry, Zhongshan School of Medicine, 
      Sun Yat-sen University, Guangzhou, 510080, China.
FAU - Lin, SuiZhen
AU  - Lin S
AD  - Guangzhou Cellprotek Pharmaceutical Co., Ltd., Guangzhou, 510663, China.
FAU - Yan, GuangMei
AU  - Yan G
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China.
FAU - Huang, YiJun
AU  - Huang Y
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      Guangzhou, 510080, China. huangyj@mail.sysu.edu.cn.
FAU - Yin, Wei
AU  - Yin W
AD  - Department of Molecular Biology and Biochemistry, Zhongshan School of Medicine, 
      Sun Yat-sen University, Guangzhou, 510080, China. yinwei@mail.sysu.edu.cn.
LA  - eng
GR  - 82071321/National Natural Science Foundation of China/
GR  - 2019-L002/Leading Talent Project in Science and Technology of Guangzhou 
      Development District/
PT  - Journal Article
DEP - 20221228
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - U78804BIDR (lonidamine)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - Inflammasomes/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - *Encephalomyelitis, Autoimmune, Experimental/drug therapy
MH  - *Multiple Sclerosis
MH  - *Sepsis
PMC - PMC9798610
OTO - NOTNLM
OT  - ASC inhibitors
OT  - Inflammasome
OT  - Ischemic stroke
OT  - Lonidamine
OT  - Multiple sclerosis
OT  - Sepsis
COIS- The authors state that the research was conducted without any commercial or 
      financial relationship that could be interpreted as a potential conflict of 
      interest.
EDAT- 2022/12/29 06:00
MHDA- 2022/12/31 06:00
PMCR- 2022/12/28
CRDT- 2022/12/28 23:42
PHST- 2022/08/01 00:00 [received]
PHST- 2022/12/22 00:00 [accepted]
PHST- 2022/12/28 23:42 [entrez]
PHST- 2022/12/29 06:00 [pubmed]
PHST- 2022/12/31 06:00 [medline]
PHST- 2022/12/28 00:00 [pmc-release]
AID - 10.1186/s12974-022-02682-w [pii]
AID - 2682 [pii]
AID - 10.1186/s12974-022-02682-w [doi]
PST - epublish
SO  - J Neuroinflammation. 2022 Dec 28;19(1):315. doi: 10.1186/s12974-022-02682-w.