Bergapten promotes angiogenesis by enhancing endothelial autophagy and reducing pyroptosis in ischemic skin flap.

Random-pattern skin flaps are commonly used in plastic surgery to close skin defects, but necrosis often occurs in the distal portions of flaps due to insufficient blood supply, which severely limits their clinical utility. Thus, we developed a vascular endothelial growth factor (VEGF)-loaded injectable hydrogel to promote local angiogenesis to improve skin flap survival. The hydrogel, composed of gelatin and low-molecular-weight hyaluronic acid, is obtained via microbial transglutaminase (mTG)-catalyzed crosslinking and hydrogen bonding. By adjusting the concentrations of gelatin and hyaluronic acid, the properties of the injectable hydrogel, including gelation time, internal pore size, swelling rate and degradation rate, were tuned and slow and sustained release of VEGF from the hydrogel was achieved. Benefiting from the ability of the gelatin-hyaluronic acid (Gel-HA) hydrogel to induce HUVEC proliferation and migration, and the enhanced bioactivity of VEGF when loaded in the Gel-HA hydrogel, the combination of Gel-HA hydrogel and VEGF synergistically promotes angiogenesis. Moreover, in a rat dorsal random skin flap model, the VEGF-loaded Gel-HA hydrogel was easily injected into the skin flap, significantly reducing necrosis and enhancing blood perfusion in skin flap areas. Therefore, this VEGF-loaded Gel-HA hydrogel could be an effective, easily prepared platform for rapid vascularization and ischemic flap repair, and it also has potential for clinical applications for other ischemic tissues.

Flap transplantation plays a vital role in wound reconstruction. However, the mechanisms by which remote ischemic preconditioning (RIPC) may improve flap survival remain incompletely understood. Rats were randomly assigned to three groups: sham, ischemia/reperfusion (I/R), and RIPC + I/R. The I/R model was established by ligating the iliopsoas and thoracodorsal arteries to induce flap ischemia, followed by reperfusion. RIPC was performed via limb clamping. A combination of high-throughput sequencing, functional cellular assays, and live imaging was used to assess gene expression, cellular functions, and flap viability. RIPC upregulated the expression of ZNF667. This protein acted as a transcriptional repressor of VHL by binding to its promoter region, where it competitively inhibited the recruitment of histone-modifying enzymes, including MLL3/4, SETD1A, and EP300. Consequently, histone methylation and acetylation were reduced, leading to suppressed VHL transcription. The downregulation of VHL diminished the ubiquitination-mediated degradation of hypoxia-inducible factor-1α (HIF-1α), which in turn enhanced the expression of stromal cell-derived factor 1 (SDF1). This signaling cascade promoted the proliferation, migration, differentiation, and tube-forming capacity of endothelial progenitor cells (EPCs). Live imaging confirmed that RIPC stimulated the recruitment of EPCs into the flap tissue, accompanied by increased microvessel density. These effects collectively enhanced angiogenesis and significantly reduced the area of flap necrosis. RIPC improves flap survival by modulating the ZNF667-VHL-SDF1 axis and augmenting the function of EPCs. These findings not only provide a potential therapeutic strategy for flap transplantation but also advance our understanding of the mechanisms underlying flap survival.

ABSTRACT Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the MT-RNR1/12S rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, in vivo overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery. Abbreviations: AA = arachidonic acid, AAV = adeno-associated virus, ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta, ALs = autolysosomes, BECN1 = beclin 1, CASP1 = caspase 1, CQ = chloroquine, CTSB = cathepsin B, CTSD = cathepsin D, CTSL = cathepsin L, Co-IP = co-immunoprecipitation, DEGs = differentially expressed genes, ELISA = enzyme-linked immunosorbent assay, F-CHP = 5-FAM-conjugated collagen hybridizing peptide staining, GSDMD = gasdermin D, GO = gene Ontology, GPT/ALT = glutamic pyruvic transaminase, soluble, GOT1/AST = glutamic-oxaloacetic transaminase 1, soluble, HE = hematoxylin-eosin, HUVECs = human umbilical vein endothelial cells, IP/MS = immunoprecipitation coupled with mass spectrometry, IL1B/IL-1β = interleukin 1 beta, IL18 = interleukin 18, IP = intraperitoneal injection, IV = intravenous injection, LDBF = laser Doppler blood flow, LMP = lysosomal membrane permeability, MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3, MAPK = mitogen-activated protein kinase, NAGLU = alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB), NFKB/NF-κB = nuclear factor kappa B, NLRP1 = NLR family pyrin domain containing 1, NLRP3 = NLR family pyrin domain containing 3, PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1, PLA2G4A/cPLA2 = phospholipase A2, group IVA (cytosolic, calcium-dependent), PYCARD/ASC = PYD and CARD domain containing, PIK3C3/VPS34 = phosphatidylinositol 3-kinase catalytic subunit type 3, PMA = phorbol 12-myristate 13-acetate, ROS = reactive oxygen speciesSQSTM1/p62 = sequestosome 1, SPR = surface plasmon resonance, scRNA-seq = single-cell RNA sequencing, UMAP = uniform manifold approximation and projection, WB = western blotting.

Overexpression of thioredoxin-1 enhances angiogenesis and survival in a mouse ischemic skin flap model.

Botulinum toxin (BoNT) is increasingly recognized for vascular effects beyond its established neuromuscular use. Evidence indicates a dose-dependent mechanism in which BoNT either promotes vasodilation and perfusion or inhibits cholinergic vasodilatory activity, making it relevant for ischemic, vasospastic, and inflammatory conditions. This review evaluates current data on the dose-dependent vascular actions of BoNT and outlines its therapeutic relevance in aesthetic and reconstructive medicine. A narrative review was performed using PubMed, MEDLINE, Embase, and Google Scholar, focusing on studies published from 2000 to 2025. Search terms combined "botulinum toxin" with "vasodilation," "ischemia," "flap survival," "angiogenesis," and related concepts. Eligible publications included clinical trials, animal studies, in vitro models, and systematic reviews assessing vascular outcomes after BoNT exposure. Of 163 records identified, 57 met inclusion criteria and were analyzed. BoNT demonstrates dual vascular mechanisms. At higher doses, it enhances perfusion and promotes angiogenesis through vascular endothelial growth factor and nitric oxide pathways, supporting applications in ischemic flaps and Raynaud's phenomenon. At lower doses, it reduces excessive cholinergic vasodilation and neurogenic inflammation, offering benefits in conditions such as rosacea and hyperhidrosis. These effects are dose-dependent and tissue-specific, with variability across experimental models. Concentrations above 20IU/ml may be considered high-dose, whereas lower levels represent low-dose BoNT. BoNT exhibits versatile vascular activity. Higher doses support vascular regeneration and angiogenesis, while lower doses modulate hyperreactive vascular responses. Further research is needed to clarify mechanisms, refine dose-response guidelines, and assess long-term safety across clinical indications to optimize its vascular applications. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Hyperbaric oxygen therapy after reconstructive breast surgery: A retrospective study.

Intraoperative microvascular complications in autologous breast reconstruction may increase the risk of immediate postoperative flap complications, such as congestion, thrombosis, and flap loss. The impact of specific intraoperative complications on patient outcomes remains unclear. A retrospective chart review of microsurgical breast reconstruction cases from 2017 to 2023 was performed to determine intraoperative and postoperative complications, as well as patient outcomes. Statistical analysis was conducted to determine associations between intraoperative complications and outcomes. A total of 1,005 flaps were performed in 620 patients, with intraoperative complications experienced in 15.1% (152/1,005) flaps. Pedicle/perforator injury was the most common (5.3%). Difficult flap pedicle dissection was a predictor of the need for a blood transfusion (17.7% vs. 8.3%, OR: 2.4 [95% CI: 1.1-5.0], p = 0.04). Hematoma was not associated with any intraoperative complications. In comparison, postoperative flap ischemia was associated only with intraoperative arterial thrombosis (8.3% vs. 0.7%, OR: 2.8 [95% CI: 1.5-113.0], p = 0.003). Postoperative flap congestion was associated with both intraoperative complications of alternate venous outflow (40% vs. 1.9%, OR: 34.4 [95% CI: 5.4-218], p = 0.004) and pedicle/perforator injury (10.5% vs. 1.9%, OR: 6.0 [95% CI: 1.3-27.7], p = 0.01). Prolonged length of stay greater than the expected 3 days was associated with difficult flap pedicle vessel dissection (52.9% vs. 31.5%, OR: 2.4 [95% CI: 1.4-4.3], p = 0.001) and intraoperative arterial thrombosis (63.6% vs. 32.3%, OR: 3.7 [95% CI: 1.1-12.7], p = 0.04). Length of stay greater than 4 days was solely associated with intraoperative thrombosis (36.4% vs. 9.9%, OR: 5.4 [1.6-18.7], p = 0.019). The intraoperative complications of venous anastomosis revision and difficult internal mammary vessel dissection had no significant association with the postoperative course. Specific intraoperative complications are associated with higher rates of postoperative complications. Awareness of the tendency for a complex postoperative recovery is warranted.

Relevance. In recent years, the number of children born with severe forms of cleft lip and palate has increased. Surgical treatment in these patients is often associated with postoperative complications, including recurrent defects of the anterior hard palate. Impaired microcirculation at the surgical site is a key factor in the pathogenesis of these complications and may result in tissue loss, delayed healing, postoperative defect formation, and the need for repeat surgery. Standard clinical assessment of flap viability based on color, turgor, and capillary refill remains subjective and lacks sufficient sensitivity for early detection of deep or central ischemia. This highlights the need for objective methods of intraoperative and postoperative monitoring. Digital vital capillaroscopy (DVC) is a promising noninvasive technique that enables objective real-time assessment of microcirculation. It allows flap monitoring, assessment of angiogenesis, detection of early signs of impaired perfusion, and prediction of the risk of flap ischemia and tissue necrosis. Understanding these processes is essential for improving tongue flap reconstruction techniques and optimizing surgical outcomes. Materials and methods. This prospective study included 15 patients aged 12–18 years with secondary anterior hard palatal defects measuring 2–4 cm 2 . All patients underwent two-stage defect closure using a thin split-thickness tongue flap. Microcirculation was assessed by DVC using the OKO device (Russia) before surgery in the defect area, donor site, and intact mucosa, and then daily from postoperative day 1 to day 16. Functional capillary density (capillaries/ mm 2 ), linear erythrocyte velocity (LEV, μm/s), and volumetric erythrocyte velocity (VEV, μm 3 /s) were assessed. Results. A three-phase pattern of microcirculatory changes was identified. In the early postoperative period (days 1–3), functional capillary density decreased to 5–8 capillaries/mm 2 , LEV to 0–50 μm/s, and VEV to 0–2,000 μm 3 /s. During the initial regeneration phase (days 4–7), the capillary network began to recover, with LEV increasing to 250–400 μm/s and VEV to 15,000–25,000 μm 3 /s. During the active healing and flap integration phase (days 8–16), these parameters stabilized, with LEV reaching 550–700 μm/s and VEV 45,000–60,000 μm 3 /s. Conclusion. DVC is a highly informative method for objective monitoring of microcirculation during healing after tongue flap reconstruction. Capillary blood flow parameters are early indicators of ischemic changes and prognostic markers of flap viability and successful integration. Dynamic DVC monitoring allows individualized therapy and helps determine the optimal timing of the second stage of surgery (postoperative days 14–16), thereby reducing the risk of complications.

Abstract Aims Free tissue transfer is a common plastic surgical procedure with a wide array of applications. There is limited consensus on how free flap ischaemia time impacts flap survival. This systematic review aims to evaluate the association between free flap ischaemia time and acute flap failure rate. Methods A systematic review and meta-analysis in compliance with PRISMA statement standards was conducted following registration on the PROSPERO Register (CRD420251052841). A search strategy was developed and the search conducted in September 2024. Studies eligible for inclusion reported length of ischaemia time for free flap surgery and acute flap failure rate. 78 articles were eligible for inclusion and were published between 1997 and 2024. Study populations ranged from 7 to 3926 patients, with a pooled total of 26 374 free flaps in 23 615 patients. The meta-analysis showed overall risk of flap failure was 3.5% (95% c.i. 3%–4.1%). Meta-regression using ischaemia time as a continuous variable showed an increasing risk of acute flap failure from 3% (2.3%–3.9%) at 30 min ischaemia time to 7.5% (4.4%–12.5%) at 240 min. The variables study type, flap type, indication and risk of bias did not account for between study heterogeneity which was substantial. Conclusions This study has systematically assessed existing literature to show a significant association between prolonged ischaemia time and acute free flap loss. This association can guide microsurgical training as carrying out microsurgery in a time efficient manner has a positive impact on free flap survival.

Background: Monitoring glucose levels in flap tissues can be a valuable indicator of flap viability and early detection of flap failure. This study aimed to analyze the utility of intra-flap glucose monitoring in predicting flap outcomes. Materials & Methods: It was a single centre, single arm, non-comparative longitudinal observational study done from May 2019 to October 2020. Thirty (31) patients, operated for reconstruction with various flap incorporating skin in the department of plastic and reconstructive surgery after taking informed written consent. Flap blood glucose levels have been measured at scheduled times by glucometer. At the same time blood glucose levels has been measured from adjacent normal skin (control site). In addition to blood glucose assessment simultaneous clinically findings have been noted and correlated. In the event of any indication of impending/frank ischemic changes appropriate measures have been taken by the surgeon in-charge. Capillary blood sample has been taken by pin prick method at the distal most part of flap. At the same time patient blood glucose level has been measured from normal skin adjacent to flap. Samples were taken in immediate postoperative period then after 1hr, 12 hr, 24 hr, 48 hr and 72 hr after operation. Results: Out of thirty-five patients, thirty were male and five were female. Among four free flaps, three were antero-lateral (ALT) fascio-cutaneous flap and one was free latissimus dorsi (LD) musculocutaneous flap. We have measured flap blood glucose and body blood glucose from control site simultaneously and then calculated flap blood glucose as a percentage of body blood glucose. Out of 35 flaps, 21 flaps have done well and no sign of ischemia was found in these flaps. Blood Glucose levels of these flaps were taken at regular intervals as per study schedule. Total 63 values have been recorded from clinically ischemic flaps. Blood glucose values of ischemic flaps were significantly low with a mean value of 35.81% of body glucose. At the intervals of immediate, 1hour, 6-hour, 24-hour, 48-hour, 72 hour, 5 days the mean values of glucose are lower in necrosed flap than survived flaps. It was found to be statistically significant (p<0.05). Conclusion: Intra-flap glucose monitoring is a reliable method for predicting flap viability. Higher glucose levels are associated with flap survival, providing a potential tool for early intervention in cases of impending flap failure.

Far-infrared irradiation suppresses pyroptosis in ischemic flaps through TRPV3-mediated activation of the A2AR/EPAC1/Rap1 signaling pathway.

Fisetin promotes ischemic flap survival by enhancing autophagy via inhibition of the PI3K/Akt/mTOR signaling pathway.

Surgical wound complications remain a major source of postoperative morbidity, particularly in the setting of tissue hypoxia, ischemia, and impaired perfusion. Hyperbaric oxygen therapy (HBOT) has emerged as an adjunctive modality aimed at enhancing tissue oxygen delivery and optimizing wound healing dynamics across diverse surgical contexts. A structured narrative review of the literature was conducted using PubMed/MEDLINE to identify clinical studies, systematic reviews, and translational investigations evaluating the role of HBOT in surgical wound healing and tissue salvage. The search included articles published from January 2000 to February 2026. Evidence was synthesized descriptively, focusing on mechanistic pathways, clinical indications, reconstructive applications, and reported outcomes. HBOT exerts therapeutic effects through multiple physiological mechanisms, including enhanced plasma-dissolved oxygen delivery, angiogenesis stimulation, fibroblast proliferation, collagen synthesis, and immunomodulation. Clinical evidence supports its use in chronic ischemic wounds, such as diabetic foot ulcers, venous leg ulcers, burn injuries, and radiation-induced tissue damage, demonstrating improved wound closure rates and reduced infection risk. In reconstructive surgery, HBOT has shown benefit in compromised grafts, ischemic flaps, traumatic soft-tissue injuries, and breast reconstruction salvage. Reported outcomes include enhanced tissue viability, reduced necrosis progression, improved graft integration, and decreased amputation rates in high-risk populations. HBOT represents a biologically active adjunct capable of enhancing surgical wound healing and tissue salvage through multifactorial regenerative mechanisms. As its applications continue to expand into reconstructive and aesthetic surgical domains, HBOT is positioned to play an increasingly integrative role within multidisciplinary perioperative care and complex wound management strategies.

Ischemic skin flap viability: in vivo study of alginate-ZIF-8 hydrogel systems with Rhizophora mangle and tannic acid.

Osthole promotes skin flap survival by inhibiting ferroptosis and alleviating pyroptosis.

Galangin enhances skin flap survival by inhibiting ferroptosis via SIRT1-mediated FOXO1 deacetylation.

INTRODUCTION . The problem of treating pressure ulcers of the greater trochanter of the femur in patients with consequences of spinal trauma remains the focus of close attention of clinicians and researchers. The complexity of the problem is primarily due to the high percentage of postoperative complications and relapses. The causes of unfavorable treatment outcomes are often defects in preoperative preparation, sometimes – imperfection of the surgical techniques chosen for treatment. Studying the spectrum of complications and predictors of pressure ulcer relapse is necessary for qualitative growth of the effectiveness of surgical treatment. The OBJECTIVE was to systematize the literature data and, based on the data of our own clinical study, to evaluate the effectiveness of various types of reconstructive plastic surgeries used to close the pressure ulcer of the greater trochanter of the femur in patients with spinal trauma. METHODS AND MATERIALS . The literature sources focused on surgical treatment of pressure ulcers of the projection of the greater trochanter of the femur were analyzed.An analysis of surgical treatment of 61 patients who underwent elective surgery for pressure ulcers of the projection of the greater trochanter of the femur was conducted. The following surgical techniques were used: spoke dermotension, plastic surgery with a free split graft, plastic surgery using two types of local skin-fat flaps and a TFL flap. RESULTS. Analysis of literature data showed that the main method of treating pressure ulcers is surgery. However, the known reconstructive plastic surgeries are far from ideal, since their use leads to such formidable complications as wound infection (from 35 to 50 %), flap ischemia (17 %), flap necrosis (12.5 %), postoperative hematomas, seromas, which are predictors of relapses. In this regard, the «best option» for treating pressure ulcers remains a subject of search.A prospective study showed that among all operated patients, the most common complications in the postoperative period were flap ischemia, wound infection, suture failure, and lymphorrhea. Such complications were recorded in 21 (34 %) of 61 patients operated on for pressure ulcers of the trochanteric region. CONCLUSION . The method of choice for treating patients with extensive pressure ulcers is reconstructive plastic surgery, which is based on the formation of skin-fat flaps and rotational skin-fascial flaps with the principles of tension-free plastic surgery. At the same time, the issue of complications such as flap ischemia, lymphorrhea and wound infection remains unresolved, which requires further scientific and practical research.

Background/Objectives: Oral and oropharyngeal cancers are highly prevalent and associated with a high mortality. The primary treatment modality is surgery with free flap reconstruction becoming the gold standard. Our study aimed to assess the anthropometric and metabolic predictors of the occurrence of postoperative complications after free flap reconstruction, and to present a PRISM (Predictive Reconstructive Index for Soft-tissue Microflaps) scoring system. Methods: This retrospective cohort study included 92 patients with advanced oral and oropharyngeal squamous cell carcinoma who underwent primary surgical treatment with microvascular free flap reconstruction between 2020 and 2024. Clinical, surgical, and biochemical parameters (operative and flap ischemia time, BMI; serum albumin, total protein, and calcium) were analyzed in relation to postoperative complications. Associations were assessed using correlation analyses and binary logistic regression. Based on the key predictive variables, the PRISM scoring system was developed to estimate perioperative risk. Results: Underweight or overweight patients showed higher complication rates (Kruskal-Wallis, p = 0.019). Longer surgeries were associated with a higher incidence of SIRS, which in turn correlated with increased flap ischemia (Man-Whitney, p = 0.032 and 0.039). Lower albumin and total protein levels on the second postoperative day were linked to more complications (Kruskal-Wallis, p = 0.001 and 0.010), as were lower calcium levels on the first postoperative day (p = 0.033). Additionally, longer hospitalization was significantly associated with complication severity (p = 0.031). The PRISM score stratified patients into low-, moderate-, and high-risk groups. Conclusions: Free flap outcomes in oral and oropharyngeal cancer are influenced by SIRS, nutritional status, and surgical factors. Longer surgeries, flap ischemia, low albumin, protein, calcium, and abnormal BMI increased the complication risk. Careful preoperative assessment, optimization of patient condition, and strategies to minimize operative time and ischemia are essential. The PRISM score may help stratify patients and guide clinical decisions.

BackgroundRandom skin flap application is considerably limited by postoperative complications, particularly distal tissue ischemia and necrosis. Melatonin, a molecule with well-documented antioxidant and cytoprotective properties, has shown promise in protecting ischemic tissues. However, its specific role in regulating ferroptosis during ischemic flap injury, as well as its safety and efficacy in primate models (a key step for clinical translation), remains to be systematically validated. In this study, we aimed to promote angiogenesis within flap tissue through exogenous melatonin administration and to inhibit ferroptosis to mitigate ischemia–reperfusion injury, presenting a novel strategy for enhancing flap survival rates.MethodsA random skin flap was constructed in C57BL/6 J mice. After melatonin treatment for seven days, the influence of melatonin on the levels of oxidative stress, iron accumulation, and mitochondrial morphology within the skin flap tissue was assessed. We used Transwell migration assays, tube formation assays, flow cytometry, and immunofluorescence staining to determine the effects of melatonin in vitro. The ferroptosis inducer erastin was used in combination with melatonin to treat random skin flap mice and tert-butyl hydroperoxide (TBHP)–induced cellular models, and the pathway through which melatonin counteracts iron mutations was explored. Lastly, we conducted experiments using nonhuman primate models and analyzed the protective effects of melatonin on ischemic flaps in macaques, highlighting its potential for clinical translation.ResultsMelatonin ameliorated the survival area of ischemic flaps in mice, enhanced angiogenesis, reduced mitochondrial damage, and also suppressed lipid peroxidation and iron ion accumulation. Melatonin attenuated TBHP-induced cell death, lipid peroxidation, and mitochondrial damage in vitro. Further mechanistic studies revealed that melatonin inhibited ferroptosis, accompanied by nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), and increases the expression of downstream gene (effector) heme oxygenase-1 (HO-1). More importantly, experiments in macaques demonstrated that melatonin could enhance flap viability and angiogenesis, and exhibited a good safety profile.ConclusionMelatonin enhanced flap viability in mice and macaques by inhibiting ferroptosis, boosting angiogenesis, and attenuating oxidative stress injury.