Anemia of Chronic Disease Revisited: Hepcidin Dysregulation, Erythropoietic Failure, and Emerging Roles of SGLT2 Inhibition

ABSTRACT Anemia of chronic disease (ACD), also referred to as anemia of inflammation, is a prevalent and clinically significant complication of chronic infection, autoimmune disease, malignancy, and chronic kidney disease. It is characterized by inflammation‐driven iron sequestration, impaired erythropoietin (EPO) production and signaling, and suppression of effective erythropoiesis. Current therapies (iron supplementation and erythropoiesis‐stimulating agents) often address downstream consequences and may be limited by hepcidin‐driven functional iron deficiency, cytokine‐mediated EPO resistance, and safety concerns in vulnerable populations. This review re‐examines ACD through an integrated framework of hepcidin dysregulation, iron sequestration, and inflammatory inhibition of the EPO axis. We then synthesize emerging evidence that sodium–glucose cotransporter 2 (SGLT2) inhibitors produce sustained increases in hemoglobin/hematocrit beyond transient hemoconcentration across cardiovascular and kidney disease trials, including in non‐diabetic populations. Mechanistic studies suggest a coordinated biologic response that may include reduced hepcidin, improved iron mobilization, physiologic augmentation of endogenous EPO, and attenuation of systemic inflammation—pathways directly relevant to ACD. We critically re‐appraise current ACD paradigms by contrasting downstream “replacement” strategies (iron and ESAs) with pathway‐level approaches (HIF‐PHIs and SGLT2 inhibition), and we outline biomarker‐guided study designs to test whether SGLT2 inhibition may act as an adjunctive physiologic modulator of iron–erythropoietic crosstalk in well‐phenotyped inflammatory anemia cohorts, while emphasizing that current evidence remains hypothesis‐generating rather than practice‐changing.