Bowen Liu

Targeting dihydroorotate dehydrogenase (DHODH) to restrict de novo pyrimidine synthesis is a promising anticancer strategy. However, the efficacy of DHODH inhibitors, such as brequinar (BQR), is often constrained by modest single-agent cytotoxicity, necessitating the exploration of combination therapies. Here, using mt-Keima-based mitophagy reporters and CRISPR/Cas9-mediated gene knockout models, we reveal a critical adaptive mechanism whereby BQR-induced mitochondrial reactive oxygen species (mtROS) trigger protective mitophagy. Crucially, we demonstrate that inhibiting this autophagy process synergistically enhances BQR’s anti-tumor activity both in vitro and in vivo . This combination leads to enhanced mtROS accumulation and severe lipid peroxidation, ultimately triggering caspase-dependent apoptosis, while ferroptosis does not appear to be the dominant mechanism under these conditions. Our findings identify mitophagy as a key mechanism of resistance to DHODH inhibition and provide a strong rationale for a combinatorial strategy to enhance the therapeutic efficacy of this class of drugs.

Extracellular vesicles (EVs) operate as chemical messengers that facilitate intercellular communication. Emerging evidence has demonstrated that lung tissue‐derived EVs play pivotal roles in pulmonary physiological processes and have potential as biomarkers and therapeutics for lung diseases. Multiple methods have been proposed for the isolation of lung tissue‐derived EVs. However, the effects of different tissue pre‐treatments on lung EV isolation and subsequent disease biomarker discovery have not yet been comprehensively investigated. In this study, we compared the physical characteristics, recovery yields, and protein compositions of EVs isolated from lung tissues using three methods based on different tissue dissociation principles. Methodologically, the beneficial roles of blood perfusion and gentle meshing were emphasized based on their impact on EV yield and purity. These results demonstrate that different methods enrich distinct subpopulations of EVs that exhibit significant differences in their protein cargo and surface properties. These disparities directly affect the diagnostic detection of marker proteins related to lung diseases, including lung tumors, asthma, and pulmonary fibrosis. Collectively, these findings highlight the variations in EV characteristics resulting from the applied approaches and offer compelling suggestions for guiding researchers in selecting a suitable isolation method based on downstream functional studies and clinical applications.

Extracellular vesicles (EVs) are nanovesicles containing bioactive molecules including proteins, nucleic acids and lipids that mediate intercellular and inter-organ communications, holding promise as potential therapeutics for multiple diseases. Adipose tissue (AT) serves as a dynamically distributed energy storage organ throughout the body, whose accumulation leads to obesity, a condition characterized by infiltration with abundant immune cells. Emerging evidence has illustrated that EVs secreted by AT are the novel class of adipokines that regulate the homeostasis between AT and peripheral organs. However, most of the studies focused on the investigations of EVs derived from adipocytes or adipose-derived stem cells (ADSCs), the summarization of functions in cellular and inter-organ crosstalk of EVs directly derived from adipose tissue (AT-EVs) are still limited. Here, we provide a systemic summary on the key components and functions of EVs derived from healthy adipose tissue, showing their significance on the tissue recovery and metabolic homeostasis regulation. Also, we discuss the harmful influences of EVs derived from obese adipose tissue on the distal organs. Furthermore, we elucidate the potential applications and constraints of EVs from healthy patients lipoaspirates as therapeutic agents, highlighting the potential of AT-EVs as a valuable biological material with broad prospects for future clinical use.

Extracellular vesicles (EVs) are single‐membrane vesicles that play an essential role in long‐range intercellular communications. EV investigation has been explored largely through cell‐culture systems, but it remains unclear how physiological EVs exert homeostatic or pathological functions in vivo. Here, we report that lung EVs promote chemotaxis of neutrophils in bone marrow through delivery of double stranded DNA (dsDNA). We have identified and characterized EVs containing dsDNA collected from both human and murine lung tissues using newly developed approaches. Our analysis of EV proteomics together with single‐cell RNA sequencing data reveals that type II alveolar epithelial cells are the main source of the lung EVs. Furthermore, we demonstrate that the lung EVs accumulate in bone marrow and enhance neutrophil recruitment under inflammation conditions. Moreover, lung EV‐DNA stimulates neutrophils to release the chemokines CXCL1 and CXCL2 via DNA‐TLR9 signalling. Our findings establish a molecular basis of lung EVs in enhancement of host immune response to bacterial infection and provide new insights into understanding of vesicle‐mediated systematic communications.