bims-evecad 2026-01-04 papers

Issue of 2026–01–04
three papers selected by
Cliff Dominy

Antioxidants (Basel). 2025 Dec 14. pii: 1504. [Epub ahead of print]14(12):

Extracellular Vesicle-Mediated Delivery of Antioxidant Enzymes: Emerging Insights and Translational Opportunities.

Junyu Wang, Yakun Li, Robin P F Dullaart, Peter Olinga, Han Moshage.

Oxidative stress is a key contributor to the onset and progression of diverse pathological conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, cardiovascular disorders, and cancer. Conventional antioxidant therapies, such as small-molecule scavengers or systemic enzyme administration, are limited by poor stability, inefficient delivery, and off-target effects. Extracellular vesicles (EVs), particularly exosomes, are increasingly recognized as natural carriers of antioxidant enzymes (AOEs), including catalase, superoxide dismutases, glutathione peroxidases, peroxiredoxins, and thioredoxin. These vesicles not only protect enzymes from degradation but also enable targeted delivery to recipient cells, where they can actively modulate redox homeostasis. In this review, we summarize current evidence for AOEs as bona fide EV cargo, outline mechanisms that govern their selective packaging and transfer, and highlight their roles in intercellular communication under physiological and pathological conditions. We also discuss emerging therapeutic applications of both natural and engineered EVs for redox modulation, along with the challenges of quantifying enzymatic activity, ensuring reproducibility, and scaling clinical translation. By integrating insights from cell biology, redox signaling, and translational research, we propose that EV-mediated AOE delivery represents a promising next-generation strategy for combating oxidative stress-related diseases.

Keywords: antioxidant enzymes (AOEs); extracellular vesicles (EVs); intercellular communication; oxidative stress; redox signaling; therapeutic delivery

DOI: https://doi.org/10.3390/antiox14121504

Int J Mol Sci. 2025 Dec 17. pii: 12123. [Epub ahead of print]26(24):

Hypoxic Small Extracellular Vesicle Preconditioning of AC16 Cardiomyocytes Increase Caspase-3 and Caspase-8 Activity During Hypoxia.

Øystein Røsand, Victoria Johansen, Gurdeep Marwarha, Morten A Høydal.

Small extracellular vesicles (sEVs) are increasingly recognized as crucial mediators of cell-cell communication. This study aims to determine the influence of sEV mediation on cardiomyocytes (CMs) under hypoxic conditions and identify the molecular modifications induced by hypoxia-derived sEVs (H-sEVs). Using a preconditional approach, we administered hypoxic AC16 CM-derived sEVs to recipient AC16 CMs before hypoxic stimulation. Molecular and biochemical analyses were performed to evaluate the biological effects of H-sEVs, e.g., cell viability assay, caspase assays, Western blotting, and quantitative sandwich ELISA. Our results showed a significant decrease in CM viability following hypoxic stimulation, as well as elevated caspase-3 and caspase-8 activity, and increased Bcl-2-associated X protein (BAX) translocation to the mitochondria followed by an increased release of Cytochrome C from mitochondria to cytosol. Preconditioning with H-sEVs further exacerbated caspase-3 and caspase-8 activation, which was explained by aggravated translocation of BAX to the mitochondria with consequences of cytochrome C release and increased apoptotic signaling. Our research indicates that sEVs secreted by hypoxic AC16 CMs negatively impact the biological properties of recipient CMs exposed to hypoxic stress. Thus, these findings widen our current understanding of sEV-mediated cellular communication during hypoxic events and provide insights into potential therapeutic targets for cardiac ischemic injury.

Keywords: apoptosis; hypoxia; myocardial ischemia; small extracellular vesicles

DOI: https://doi.org/10.3390/ijms262412123

J Adv Res. 2025 Dec 28. pii: S2090-1232(25)01042-2. [Epub ahead of print]

Thbs1+ extracellular vesicles from irradiated tumors induce cardiac wasting via PERK-eIF2α-Atf4 signaling.

Song Gao, Wenzhi Liu, Jingquan He, Zhirui Shan, Yue Wang, Tian Li, Zicheng Zhang.

AIMS: Cardiac muscle wasting is a significant complication observed in lung cancer patients receiving radiotherapy. Radiotherapy, a commonly used anticancer treatment, is known to cause cardiovascular complications; however, the mechanisms linking tumor irradiation to cardiac wasting remain poorly understood.
METHODS: Lewis lung carcinoma (LLC) and CT26 tumor-bearing mice received localized tumor irradiation. Conditioned medium or EVs from irradiated tumor cells were collected and used to treat HL-1 cardiomyocytes. Autophagy, protein synthesis, and atrophy were assessed. The roles of tumor Thbs1 and cardiac PERK signaling were determined via shRNA-mediated knockdown and PERK mutation in vitro and in vivo.
RESULTS: We demonstrated that localized tumor irradiation induces cardiac muscle wasting in mice, which is associated with PERK-eIF2α-Atf4 pathway activation and increased Thbs1 protein-but not mRNA-levels in cardiomyocytes. Mechanistically, Thbs1 is delivered via extracellular vesicles (EVs) derived from irradiated tumors. Tumor-derived Thbs1+ EVs are necessary and sufficient to trigger autophagy, suppress protein synthesis, and cause atrophy in cardiomyocytes, which is dependent on the Thbs1-PERK interaction and downstream signaling.
CONCLUSION: These results indicate that radiotherapy promotes the release of Thbs1+ EVs, which drive cardiac muscle wasting via PERK-eIF2α-Atf4 signaling, revealing a novel mechanism underlying cancer-associated cardiac damage.

Keywords: Autophagy; Cardiac muscle wasting; Extracellular vesicles; Protein synthesis; Radiotherapy

DOI: https://doi.org/10.1016/j.jare.2025.12.053