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Hematopoietic stem cells (HSCs) produce mature blood cells throughout lifetime. Natural genetic diversity offers an important yet largely untapped reservoir for deciphering regulatory mechanisms of HSCs and hematopoiesis. In this review, we explore the role of latexin, identified by natural variation, in regulating homeostatic and stress hematopoiesis, unravel the underlying signaling pathways, and propose its therapeutic implication.Latexin acts endogenously in HSCs to negatively regulate their population size by enhancing apoptosis and by decreasing self-renewal. Deletion of latexin in vivo increases HSC repopulation capacity and survival, expands the entire hematopoietic system, and mitigates myelosuppression. Latexin inactivation downregulates thrombospondin 1 (Thbs1). It inhibits nuclear translocation of ribosomal protein subunit 3 (Rps3), a novel latexin-binding protein, and sensitizes hematopoietic cells to radiation-induced cell death. However, how latexin-Rps3 pathway regulates Thbs1 transcription is unclear. Latexin is downregulated in cancer cells because of promoter hypermethylation, but latexin-depleted mice do not inherently develop hematologic malignancies even with aging. The mechanism of action of latexin in tumorigenesis remains largely unknown.Understanding how latexin regulates HSC survival, self-renewal, and stress response will advance our knowledge of HSC biology. It will facilitate the development of a novel therapeutic strategy for hematopoietic regeneration and cancer treatment.