PXD053870

PXD053870 is an original dataset announced via ProteomeXchange.

Title	Selective and direct targeting of the AdipoR2-CaM-CaMKII-NOS3 axis as a rapid-acting therapy for advanced acute liver failure
Description	Drug-induced liver injuries often progress to acute liver failure (ALF) with a high mortality rate. Once ALF has commenced, therapy is minimal. Here, we report that the small bioactive compound SCM-198 (4-guanidino-n-butyl syringate) enables 100% survival of ALF mice induced by paracetamol (APAP) or thioacetamide (TAA) overdoes, even given therapeutically after the establishment of ALF. SCM-198 rapidly recovers liver functions within 6 hours. Using affinity purification and LC-MS, we identify that adiponectin receptor 2 (AdipoR2), but not AdipoR1, is a selective target of SCM-198 mediating the hepatoprotection function of SCM-198. AdipoR2 interacts with SCM-198 through the R335 residues, forming putative guanidine-arginine pairing, with a dissociation constant of 2.3 µM determined by MST and SPR. SCM-198-AdipoR2 does not signal through the AMPK or mTOR pathways, but by increasing the activity of a newly identified AdipoR2-CaM-CaMKII-NOS3 complex, which is pre-exited in liver cells. SCM-198-AdipoR2 binding causes Ca2+ influx and restores the phosphorylation level of CaMKII and NOS3, with the Y274 residue of AdipoR2 serving as a molecular switch for Ca2+ influx. This enables the rapid action of SCM-198 in regulating the levels of nitric oxide (NO) for liver protection in wild type, but not in Adipor2-/- or NOS3-/- mice. Moderately elevated NO attenuates inflammation, regulates lipid metabolism, and stimulates cell proliferation. SCM-198-activation of AdipoR2 also protects human ESC-derived liver organoids from oxidative stress, APAP, or TAA injuries. Together, these results demonstrate that selective targeting of the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 is a rapid-acting therapeutic strategy for ALF, both in mouse models and human organoid models, and provides an avenue for selective regulation of AdipoR2 signal transduction in organ regeneration and repair.
HostingRepository	iProX
AnnounceDate	2024-07-11
AnnouncementXML	Submission_2024-11-25_18:12:32.505.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Youwei Chen
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090; scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro; TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-10 21:33:22	ID requested
⏵ 1	2024-11-25 18:12:32	announced

Dataset with its publication pending

submitter keyword: acute liver failure, AdipoR2, CaM, NOS3, Nitric acid, Ca2+ influx, CaM, therapeutic

Gufa Lin
contact affiliation	Tongji University
contact email	lingufa@tongji.edu.cn
lab head
Youwei Chen
contact affiliation	Tongji University
contact email	chenyouwei@tongji.edu.cn
dataset submitter

iProX dataset URI