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When activated, the IRR initiates several critical cytoprotective cascades: JAK2/STAT3 and STAT5 signalling promoting anti-apoptotic gene expression and cellular survival PI3K/Akt pathway suppressing pro-apoptotic factors and promoting neuronal and endothelial cell survival NF-B modulation reducing pro-inflammatory cytokine production including TNF-, IL-1, and IL-6 MAPK/ERK activation supporting cellular repair and adaptive stress responses Anti-oxidant pathway upregulation reducing oxidative damage in metabolically stressed cells ARA-290s selective activation of the IRR without EPOR homodimer engagement allows researchers to study all of the above pathways without the erythropoietic confound present in full-length EPO studies

1 Introduction Excessive alcohol consumption is a major global health issue, with ALD accounting for a significant proportion of alcohol-related fatalities (Mackowiak et al., 2024