PXD046469-1

PXD046469 is an original dataset announced via ProteomeXchange.

Title	iRhom2 regulates HMGB1 secretion to modulate inflammation and hepatocyte senescence in an in vitro model of ischemia/reperfusion injury
Description	Background and Aims: Ischemia/reperfusion injury (IRI), considered one of the most important causes of liver organ rejection in acute and chronic phases, generates an inflammatory environment leading to compromised allograft functionality and rejection. In the last ten years, iRhom2 emerged as an essential regulator of tumor necrosis factor  (TNFα) release by controlling the activity of TNFα converting enzyme (TACE), thus implying its involvement in several inflammatory diseases. Our goal was to investigate iRhom2 function in IRI since no data have been described yet on its potential role in the insurgence of the injury. Methods: We analyzed iRhom2 expression in a cohort of 48 patients undergoing liver transplants (OT). We then study iRhom2 function via siRNA and CRISPR/Cas9 technology in macrophages subjected to in vitro IRI model. We used proteomics and cell biology assays to determine iRhom2 function during in vitro IRI. Finally, we used a novel in vitro IRI protocol to study the effects of iRhom2-ablated macrophages co-culture with hepatocytes. Results: We demonstrated that iRhom2 is involved in liver IRI progression in transplanted patients, and its downregulation modulates the secretion of pro-inflammatory cytokines, including HMGB1, in M1-like primary macrophages. Our findings showed that HMGB1 is secreted in an iRhom2-dependent manner and in a TACE-independent fashion, thus inducing IRI-associated senescence phenotype on injured hepatocytes. Conclusions: Our results show that HMGB1 iRhom2-dependent secretion is required to induce IRI-associated senescence phenotype on IRI-cultured hepatocytes. Thus, iRhom2 inhibition during IRI might represent a promising target to improve recovery from the damage and may prevent the development of late-onset allograft rejection by tackling the damage from two different aspects: TNF-dependent inflammation and HMGB1-dependent hepatocyte senescence.
HostingRepository	PRIDE
AnnounceDate	2025-07-21
AnnouncementXML	Submission_2025-07-21_08:53:05.349.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Matteo Calligaris
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-28 05:54:09	ID requested
⏵ 1	2025-07-21 08:53:05	announced

Dataset with its publication pending

submitter keyword: liver transplant

ischemia/reperfusion

inflammation

iRhom2

HMGB1

cellular senescence

secretomics.

Simone Dario Scilabra
contact affiliation	Proteomic lab., Fondazione Ri.MED
contact email	sdscilabra@fondazionerimed.com
lab head
Matteo Calligaris
contact affiliation	Università di Udine
contact email	matteo.calligaris@uniud.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046469
     1. Label: PRIDE project
     2. Name: iRhom2 regulates HMGB1 secretion to modulate inflammation and hepatocyte senescence in an in vitro model of ischemia/reperfusion injury