In a groundbreaking study set to reshape our understanding of blood diseases and cancer biology, researchers have unveiled the pivotal role of succinate receptor 1 (SUCNR1) in regulating hematopoiesis and staving off the progression of acute myeloid leukemia (AML). Published in Nature Communications in 2026, this research elucidates how SUCNR1 serves as a metabolic sentinel, intricately balancing the bone marrow environment to prevent the uncontrolled proliferation of malignant cells. This discovery not only deepens the molecular insight of hematopoietic regulation but also heralds new avenues for therapeutic intervention in leukemia.
Hematopoiesis, the lifelong process of blood cell formation, is exquisitely regulated by a complex interplay of cellular signals and molecular pathways. Disruption in this delicate equilibrium often culminates in hematological malignancies such as AML, a fast-progressing cancer characterized by the accumulation of immature myeloid cells. Despite advances in chemotherapy and targeted therapies, relapse rates and treatment resistance remain high, necessitating the identification of novel molecular targets that can modulate disease progression more effectively.
Succinate, a key intermediate of the tricarboxylic acid (TCA) cycle, has recently gained attention beyond its metabolic function for its extracellular signaling capacity through SUCNR1, also known as GPR91. This G protein-coupled receptor mediates various physiological responses, including blood pressure regulation and immune cell activation. Cuminetti, Boet, Heugel, and colleagues have now revealed that SUCNR1 is a critical checkpoint in hematopoietic stem and progenitor cell (HSPC) regulation, with profound implications for AML biology.
Through an elegant series of in vivo and in vitro experiments, the research team demonstrated that SUCNR1 activation imposes a restrictive effect on HSPC expansion. They found that succinate accumulation, often a hallmark of metabolic dysregulation in the bone marrow niche, signals through SUCNR1 to maintain hematopoietic homeostasis by enforcing quiescence on progenitor populations. This mechanism effectively prevents excessive proliferation that can predispose cells to malignant transformation.
Moreover, the study uncovered that the lack or inhibition of SUCNR1 disrupts this metabolic checkpoint, leading to aberrant hematopoietic proliferation and an accelerated progression of AML. Using genetically engineered mouse models deficient in SUCNR1, the researchers observed a striking increase in leukemic burden, alongside dysregulated hematopoiesis, culminating in worsened survival outcomes. This provided compelling evidence that SUCNR1 acts as a natural tumor suppressor within the hematopoietic system.
At the cellular signaling level, SUCNR1 engagement modulates downstream pathways involved in cell cycle regulation, apoptosis, and differentiation. The researchers highlighted its role in modulating the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways, which are crucial for cellular energy sensing and proliferation control. Succinate binding to SUCNR1 triggered a signaling cascade that culminated in the activation of these metabolic checkpoints, thereby ensuring cellular integrity.
Interestingly, the study also showed that leukemic blasts themselves alter succinate levels in the bone marrow microenvironment, suggesting a feedback loop where tumor metabolism influences disease progression. This crosstalk between cancer metabolism and signaling receptors emphasizes the dynamic interplay that drives AML pathogenesis and resistance to therapy.
The therapeutic implications are profound. By targeting SUCNR1 or modulating its signaling axis, it might be possible to restore controlled hematopoiesis and inhibit leukemic expansion. The authors propose that pharmacological agents enhancing SUCNR1 activity could serve as adjuncts to existing chemotherapies, potentially reducing relapse rates and improving patient outcomes. Conversely, metabolic interventions that alter succinate levels might also recalibrate SUCNR1-mediated signaling.
Importantly, the research dispels prior ambiguity around the role of succinate in cancer, challenging the simplistic view of succinate solely as an oncometabolite. Instead, it positions succinate as a nuanced metabolic messenger with context-dependent roles, underscoring the complexity of metabolic regulation in cancer biology.
This work also opens avenues for biomarker development. Measuring succinate levels or SUCNR1 expression in patients with AML could aid in disease stratification and monitoring therapeutic responses. Given the receptor’s accessibility as a G protein-coupled receptor, it is an attractive candidate for drug development, as many existing pharmaceuticals target this receptor family.
Furthermore, the study offers insights into the broader implications of metabolic signaling in stem cell biology and malignancies. It suggests that similar metabolic checkpoints may exist in other stem cell compartments, highlighting metabolism as a universal yet finely tuned regulator of stemness and differentiation.
By combining advanced genetic models, metabolomic profiling, and mechanistic biochemistry, Cuminetti and colleagues provide a comprehensive blueprint of how SUCNR1 orchestrates hematopoiesis and suppresses leukemia. Their multidisciplinary approach underscores the importance of integrating metabolism and signaling in cancer research.
As AML continues to pose significant clinical challenges, this research injects fresh optimism into the field. The identification of SUCNR1 as a gatekeeper in hematopoiesis not only enriches fundamental biology but also translates directly into new therapeutic strategies that could transform patient care.
In conclusion, the discovery of SUCNR1’s role in restricting hematopoietic proliferation and preventing AML progression embodies a paradigm shift. It bridges metabolism, receptor signaling, and cancer biology in an unprecedented manner. Future studies will undoubtedly explore the therapeutic potential of this receptor, potentially heralding a new class of metabolic-based therapies that reshape the treatment landscape for AML and beyond.
Subject of Research: Succinate receptor 1 (SUCNR1) in hematopoiesis regulation and acute myeloid leukemia progression
Article Title: Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression
Article References:
Cuminetti, V., Boet, E., Heugel, M. et al. Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68906-2
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