Structural insights into HRI kinase activity and inhibition

Min Cao; Glenn R Masson

doi:10.1042/BST20250541

Structural insights into HRI kinase activity and inhibition

Min Cao
, Glenn R Masson (Lead / Corresponding author)

Research output: Contribution to journal › Review article › peer-review

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Abstract

Haem-regulated inhibitor (HRI) is emerging as a potential therapeutic target in several disease areas, including cancers such as multiple myeloma and neurodegenerative disease. As one of four related mammalian kinases that phosphorylate the mRNA translation machinery substrate eIF2α, it has a central role in sensing several disparate proteotoxic stresses and preventing subsequent rounds of protein production. In this review, we will examine the latest research on the structural and molecular basis of HRI inhibition and activation, examining both regulatory biological interactions with proteins and cofactors. What emerges is that despite almost 75 years since the first identification of HRI, we still know remarkably little about how this kinase functions and is regulated.

Original language	English
Pages (from-to)	561-569
Number of pages	9
Journal	Biochemical Society Transactions
Volume	54
Issue number	5
DOIs	https://doi.org/10.1042/BST20250541
Publication status	Published - 15 May 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

DELE1-CTD
HRI
ISR
eIF2alpha
haem
kinases

ASJC Scopus subject areas

Biochemistry

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10.1042/BST20250541Licence: CC BY

Final published version
©2026 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Final published version, 3.04 MBLicence: CC BY

Cite this

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AU - Masson, Glenn R

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AB - Haem-regulated inhibitor (HRI) is emerging as a potential therapeutic target in several disease areas, including cancers such as multiple myeloma and neurodegenerative disease. As one of four related mammalian kinases that phosphorylate the mRNA translation machinery substrate eIF2α, it has a central role in sensing several disparate proteotoxic stresses and preventing subsequent rounds of protein production. In this review, we will examine the latest research on the structural and molecular basis of HRI inhibition and activation, examining both regulatory biological interactions with proteins and cofactors. What emerges is that despite almost 75 years since the first identification of HRI, we still know remarkably little about how this kinase functions and is regulated.

KW - DELE1-CTD

KW - HRI

KW - ISR

KW - eIF2alpha

KW - haem

KW - kinases

U2 - 10.1042/BST20250541

DO - 10.1042/BST20250541

M3 - Review article

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SP - 561

EP - 569

JO - Biochemical Society Transactions

JF - Biochemical Society Transactions

IS - 5

ER -

Structural insights into HRI kinase activity and inhibition

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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