DataVXAdvanced SciencePaper
journal article·2025-09Open access

Lysosome‐Featured Cell Aggregate‐Released Extracellular Vesicles Regulate Iron Homeostasis and Alleviate Post‐Irradiation Endothelial Ferroptosis for Mandibular Regeneration

Yuan‐Yuan Li, Bo Ma, Jia‐Wei Lu, Kai‐Chao Zhang, Chao Ma, Sheng‐Feng Bai, Yan‐Jiao Li, Si‐Qi Ying, Wei‐Zong Weng, Kai Zhang, Xi‐Wang Hu, Rang Li, Chen‐Xi Zheng, Xiao‐Ru Xu, Ji Chen, Fang Jin, Hao‐Kun Xu, Jian‐Wei Xie, Yan Jin, Yi Shuai, Bing‐Dong Sui

Advanced Science· Volume 12· Issue 34
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Abstract

Abstract Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, is implicated in various diseases, but effective therapeutic strategies remain limited. Lysosomal impairments cause iron dysregulation and initiate ferroptosis, which potentially contribute to ionizing radiation‐induced tissue damages. Here, the role of intercellular lysosomal regulation in governing iron homeostasis and protecting against ferroptosis is investigated in models of stem cell aggregation and mandibular regeneration post‐irradiation. Lysosomes are discovered to accumulate in specific regions within multi‐stem cell aggregates and regulate cell aggregate formation based on iron control, which is occurred through hypoxic signaling‐driven lysosomal redistribution mediated by extracellular vesicles. These vesicles exhibit lysosomal features and possess iron‐regulating properties, which rescue lysosomal defects to restore iron homeostasis and mitigate ferroptosis in recipient endothelial cells against the irradiation challenge. Based on lysosomal regulation and anti‐ferroptosis, these cell aggregate‐released extracellular vesicles (CA‐EVs) stimulate the growth of CD31 + endomucin + specialized vessels despite irradiation both in vitro and in vivo, which further promote bone regeneration of post‐irradiation mandibular defect. These findings highlight the potential of taking CA‐EVs as natural therapeutic agents to safeguard lysosomal function, modulate iron metabolism, and protect against ferroptosis, paving an avenue for combating post‐irradiation endothelial injuries and enhancing tissue regeneration.
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Research context

OpenAlex topics: Extracellular vesicles in disease · Ferroptosis and cancer prognosis · RNA modifications and cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

Department of General Dentistry Xiamen University Affiliated Chenggong Hospital Xiamen Fujian 361001 China

State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi Clinical Research Center for Oral Diseases Department of Orthodontics School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

Laboratory of Toxicant Analysis Academy of Military Medical Sciences Beijing 100850 China

Department of Orthopedics Xiamen University Affiliated Chenggong Hospital Xiamen Fujian 361001 China

State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

School of Stomatology Xi'an Medical University Xi'an Shaanxi 710021 China

Department of Stomatology Jinling Hospital Affiliated Hospital of Medical School Nanjing University Nanjing Jiangsu 210002 China

Department of Stomatology General Hospital of Eastern Theater Command Nanjing Jiangsu 210002 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · China Postdoctoral Science Foundation · Natural Science Basic Research Program of Shaanxi Province

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