[Erythroid differentiation: regulatory mechanisms and translational applications]

Erythrocytes support tissue oxygen-dependent energy metabolism by enabling oxygen transport and are essential for maintaining metabolic homeostasis. Their differentiation and development are orchestrated by multilayered regulatory networks that play a decisive role in sustaining hematopoietic homeostasis. Although key regulators and signaling pathways governing erythropoiesis have been extensively characterized, how these mechanisms are integrated across developmental transitions, stress responses, and disease states remains incompletely understood. Here, we provide a comprehensive overview of the structural basis, developmental programs, and regulatory logic of erythropoiesis. We first summarize the structural features of erythrocytes, with a focus on the membrane skeleton and its spatiotemporal assembly and relevant regulatory mechanisms. We then outline the developmental trajectories and stage-specific characteristics of erythropoiesis under both steady-state and stress conditions. Building on this framework, we integrate current knowledge on the multilayered regulatory networks governing erythropoiesis, including transcriptional control, epigenetic regulation, metabolic reprogramming, and signals from the hematopoietic microenvironment. Furthermore, using representative erythrocyte-related disorders as a lens, we discuss how dysregulation of these pathways contributes to disease pathogenesis. Finally, we highlight recent advances and key challenges in the translational applications of erythrocytes, including in vitro generation, drug delivery, immunomodulation, and regenerative medicine. This review aims to establish an integrated conceptual framework for erythroid development and to provide insights for future mechanistic studies and clinical translation.