Xiao-Ming Yang

High-dose total body irradiation (TBI) causes severe acute radiation syndrome (ARS), and bone marrow transplantation (BMT) alone often fails due to poor engraftment. Here, we evaluated whether the TLR5 agonist CBLB502 combined with BMT improves outcomes after supralethal TBI in mice. Mice received lethal TBI followed by BMT with or without CBLB502. Survival, donor hematopoietic recovery, hematopoietic stem and progenitor cell (HSPC) expansion, and cytokine profiles were assessed. CBLB502 alone failed to rescue mice, but combined with BMT markedly improved survival, even following 10 Gy irradiation, and reduced the donor cell dose required for rescue. CBLB502 promoted donor HSPC expansion in bone marrow and spleen, and remodeled the cytokine network by upregulating IL-6, G-CSF, SCF, IL-1ra, EGF, and others without inducing TNF-α. Collectively, our results indicate that CBLB502-augmented BMT represents a promising therapeutic strategy for severe ARS.

Hematopoietic stem cells (HSCs) constitute the pivotal cellular subset sustaining long-term hematopoietic homeostasis, characterized by robust self‑renewal and multilineage differentiation potential. Under physiological conditions, HSCs undergo stepwise differentiation through rigorously controlled regulatory networks to produce a full repertoire of mature blood cells, fulfilling basal physiological demands. Upon exposure to stress or pathological insults (e.g., bone marrow niche dysregulation), HSCs rapidly activate emergency regenerative programs to reconstitute hematopoietic function and restore systemic homeostasis. As intracellular "powerhouses" and central hubs of metabolic regulation, mitochondria exert profound regulatory effects on HSCs fate determination. The dynamic balance of mitochondrial metabolism not only furnishes HSCs with sufficient bioenergy but also generates critical metabolic intermediates; meanwhile, the fine-tuning of oxidative stress and autophagic machinery ensures mitochondrial network integrity. These biological processes are intricately intertwined, forming a complex regulatory network that profoundly modulates HSCs self-renewal, lineage commitment, and long-term hematopoietic reconstitution potential. This review systematically dissects the multi-dimensional regulatory mechanisms by which mitochondria govern HSCs, elaborates on the synergistic interactions and antagonistic effects among distinct components of the regulatory circuitry, and defines the pivotal role of mitochondria in sustaining HSCs homeostasis and orchestrating their repair responses to cellular damage. This work establishes a novel theoretical framework for devising mitochondrial-targeted interventions to sustain metabolic homeostasis in HSCs. Furthermore, it lays a solid scientific foundation for the treatment of hematological diseases and the development of precision therapeutic strategies, offering new insights into the clinical management of hematopoietic disorders.

Hematopoietic stem and progenitor cells (HSPCs) are crucial for blood production and regeneration. While their function is known to be regulated by diverse

Inhibition of endothelial cell (EC) death is essential for normal angiogenesis. The E3 ubiquitin ligase HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), is particularly important for EC survival during embryogenesis. The stability of HOIP is critical for LUBAC function. However, the mechanisms underlying the regulation of HOIP stability are largely unknown. Here, we uncovered a novel role of G protein pathway suppressor 2 (GPS2) in regulating EC survival and embryonic vascularization via control of HOIP stability. EC-specific GPS2 deletion mice (Gps2^ECKO) are embryonic lethal at embryonic day 16.5 (E16.5) due to defective vascularization. Deficiency of GPS2 in ECs results in aberrant TNFR1-mediated cell death. TNFR1 deletion in Gps2^ECKO mice restores normal vascularization and rescues embryonic lethality. At the molecular level, GPS2 binds to the NZF domain of HOIP and inhibits K48-linked polyubiquitination of HOIP at K579, K737, and K988 residues. GPS2 prevents HOIP proteasomal degradation and thus maintains LUBAC stability and activity. GPS2 deficiency in ECs leads to HOIP degradation and LUBAC instability, which in turn attenuates TNF-induced NF-κB activation and exacerbates the formation of the cell-death-inducing complex-II, ultimately increasing EC death. Overall, our data demonstrate that GPS2 is required for maintaining vascular integrity during embryogenesis by inhibiting TNFR1-mediated EC death via stabilizing HOIP.

Radiological or nuclear accidents can lead to serious outcomes for individuals exposed to ionizing radiation, with health effects that are either acute or delayed, deterministic or stochastic, depending on the effective dose of exposure. Mechanistically, ionizing radiation can inflict damage either directly on DNA or through oxidative stress, which may trigger a cascade of damages to tissues and organs. The development of effective radiation medical countermeasures is an unmet need and should be a top priority in preparing for radiation emergencies. This paper aims to address the critical questions of whether current countermeasures are available, what additional measures are needed, and what actions can be taken to enhance the development of radiation medical countermeasures from a systematic perspective.

NOD-, LRR-, and pyrin domain–containing protein 3 (NLRP3) has a fundamental role in host defense and is involved in diverse inflammatory diseases. NLRP3 protein expression is tightly controlled by the ubiquitin system. In particular, NLRP3 protein degradation has been extensively studied. In contrast, the mechanisms to stabilize NLRP3 protein are much less known. Here, we demonstrated the critical role of ubiquitin-specific protease 13 (USP13) in regulating NLRP3 protein stability and inflammasome activation independently of its deubiquitinating enzyme activity. USP13 competes with E3 ubiquitin ligase TRIM31 to interact with NLRP3 and prevents TRIM31-mediated NLRP3 ubiquitination at K192 and K496 sites, thereby inhibiting proteasomal degradation of NLRP3. USP13 deficiency reduces NLRP3 protein expression in both human and mouse macrophages, which consequently inhibits NLRP3 inflammasome assembly and activation. Accordingly, deficiency of USP13 attenuates monosodium urate crystal–induced mouse peritonitis. Overall, our findings reveal a previously unrecognized regulatory mechanism of NLRP3 stability by USP13 and provide a potential therapeutic target for NLRP3-driven diseases.

BRCC3 isopeptidase complex (BRISC) is a JAMM subfamily deubiquitinase that has been revealed to be required for optional activation of NLRP3 inflammasome and TLR4/NF-κB signaling pathway. BRISC plays an important role in lipopolysaccharide (LPS)/D-galactosamine-induced acute liver failure, while its functional contribution to alcoholic liver disease (ALD) is still unclear. In this study, we found that the expression of BRISC components was increased in liver tissues of alcoholic hepatitis (AH) animal models and patients with AH. Mice lacking either the scaffold subunit ABRO1 or the catalytic subunit BRCC3 showed attenuated liver steatosis, inflammation, and liver injury compared to control mice after chronic plus binge ethanol feeding. Moreover, pharmacological inhibition of BRISC activity by a BRISC inhibitor thiolutin potently protected mice from ALD development. Preliminary mechanistical studies showed that BRISC deficiency did not directly affect alcohol-induced hepatocyte injury or the translocation of LPS through the damaged gut mucosa after ethanol feeding, but prevented alcohol-induced NLRP3 inflammasome activation in liver. Collectively, our work revealed a previously unknown role of BRISC in ALD and suggested that BRISC may serve as a promising therapeutic target for ALD treatment.