In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.

Micronized extracellular matrix (mECM) comprises a class of micron-scale particulate biomaterials derived from native extracellular matrix or decellularized extracellular matrix. Compared with conventional bulk ECM/dECM scaffolds, mECM offers distinct advantages in injectability, local conformability, and integration into composite systems, making it increasingly attractive for tissue repair and regenerative medicine. This review systematically summarizes the fundamental concept, material characteristics, and major mechanisms through which mECM facilitates tissue repair, including the regulation of cell behavior via biomimetic microenvironments, modulation of the immune microenvironment, and the retention, presentation, and delivery of bioactive cues. Recent advances in the application of mECM for the repair of skin and soft tissue, musculoskeletal, cardiovascular, and neural tissues are also discussed. Collectively, mECM should not be viewed merely as a micronized form of conventional ECM materials, but rather as a functional biomaterial platform that integrates biological activity with engineering adaptability. With continued progress in mechanistic understanding and the standardization of preparation and evaluation strategies, mECM is expected to open new avenues for the clinical translation of ECM-derived biomaterials.

Despite advances in antiretroviral therapy (ART), HIV-1 cure efforts remain hindered by viral persistence in long-lived myeloid cells and immune-privileged tissues that are poorly accessible and therefore unlikely to be assessed in human clinical trials. Consequently, robust research platforms, such as immune-cell humanized mice, are needed to bridge preclinical and clinical HIV research. However, previously described humanized mouse models often show incomplete hematopoietic development, particularly showing low levels of NK or myeloid cells. Herein, we evaluate a humanized FLT3 mouse model that develops NK cells, myeloid progenitors, monocytes, and both conventional (cDCs) and plasmacytoid dendritic cells (pDCs), and assessed its capacity to support HIV-1 infection, persistence, and viral rebound. Human cord blood derived CD34[+] hematopoietic stem cells (HSC) were engrafted in FLT3 (Hu-FLT3) and NSG (Hu-NSG) mouse strains for comparison. While Hu-NSG and Hu-FLT3 mice showed comparable human lymphocyte levels, the proportion of myeloid-enriched populations, including monocytes, pDCs and cDCs, was three-fold higher in Hu-FLT3 mice (16.2 %) than in Hu-NSG mice (5.6 %), and the proportion of NK cells was six-fold higher (12.8 % vs. 1.9 %). Both strains supported HIV-1 infection, maintained viral replication for 17 weeks in untreated animals, and had detectable proviral DNA in peripheral blood, bone marrow and spleen. Oral ART reduced plasma HIV-1 RNA to undetectable levels within four weeks in both strains. After treatment discontinuation, viral rebound occurred within three weeks and approached pre-ART levels, consistent with rebound kinetics observed after treatment interruption in people living with HIV (PLWH). Human immune cells and HIV-1 RNA were more abundant in tissues from Hu-FLT3 mice than in Hu-NSG mice. This study establishes Hu‑FLT3 mice as a novel, robust and accessible in vivo platform to investigate potential HIV cure and persistence‑targeting interventions with translational relevance to human therapeutic development thanks to the improved and more complete human immune repertoire in Hu-FLT3.

Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive phenotype, molecular heterogeneity, and lack of specific therapeutic targets. To address these limitations and align with emerging personalized medicine strategies, a multifunctional liposomal nanocarrier (RELIB) was developed to co-encapsulate the chemotherapeutic alkaloid Boldine and the near-infrared (NIR)-responsive photothermal dye IR775, enabling combined chemo-photothermal therapy with tunable therapeutic potential. RELIB nanoparticles (RELIB NPs) (∼200 nm) demonstrated high encapsulation efficiency and effective photothermal conversion under NIR irradiation. In vitro studies in 4T1 cells revealed enhanced cellular internalization, selective cytotoxicity, induction of apoptosis, mitochondrial membrane depolarization, DNA damage, and inhibition of migration and clonogenic survival. Importantly, RELIB exhibited favorable biocompatibility in Zebrafish (Danio rerio) and Drosophila melanogaster models. In vivo evaluation in 4T1 tumor-bearing mice showed significant tumor regression upon NIR irradiation, with minimal systemic toxicity. Metabolomic profiling further indicated reprogramming of key pathways involved in apoptotic signaling and tumor suppression, suggesting the potential to use metabolic signatures to guide treatment response. Notably, Boldine conferred cyto-protection in normal cells, preserving cellular homeostasis and highlighting the platform's selective targeting capacity. Collectively, these findings position RELIB as a promising, biocompatible, and adaptable nanotherapeutic system with strong potential for personalized intervention in TNBC.

Diabetic kidney disease (DKD) is a major driver of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Despite existing therapeutic approaches, significant residual risk persists, highlighting the need for improved treatment strategies. TLR4 and AT1R signaling pathways play critical roles in DKD pathogenesis. The present study investigates the therapeutic potential of a novel ligustrazine-telmisartan combination in both in-vivo and in-vitro models of DKD. The streptozotocin (55 mg/kg, i.p.) was administered in Sprague-Dawley rats to induce Type-1 diabetes. After four weeks, animals were treated with ligustrazine (40 and 80 mg/kg/day, i.p.), telmisartan (10 mg/kg/day, p.o.), and combination (ligustrazine 40 mg/kg/day, i.p. + telmisartan 5 mg/kg/day, p.o.). Post-treatment, plasma, urine, and kidney tissues were collected and analyzed for biochemical, histological, and immunohistochemical parameters. In-vitro, high-glucose-rh-TGF-β1-stimulated NRK-52E cells were treated with ligustrazine-50 µM, telmisartan-10µM, and their combination, alongside TAK-242-100nM (TLR4 inhibitor control), and cell samples were processed for cell viability, morphology, immunocytochemistry and immunoblotting. The ligustrazine-telmisartan combination therapy significantly improved metabolic and renal function, while histology revealed notable preservation of renal architecture. The co-treatment significantly suppressed TLR4/NF-κB/NLRP3, AT1R/TGF-β/β-catenin, along with IL-18, IL-1β, and caspase-1 in diabetic rats, as revealed by immunohistochemistry and qRT-PCR. Moreover, co-treatment reduced TLR4, p-NF-κB, α-SMA, vimentin, and collagen I expression in NRK-52E cells as assessed by immunocytochemistry and immunoblotting. Collectively, the combination therapy showed greater anti-inflammatory and antifibrotic potential than monotherapies. These findings indicate that ligustrazine with telmisartan enhances renoprotection and allows a lower telmisartan dose, potentially reducing its side effects and improving overall therapeutic outcomes in DKD.

Pulmonary fibrosis is a progressive and often fatal lung disorder whose clinical behavior is not fully explained by conventional injury-driven models. Fibrosis frequently progresses after the initiating insult has resolved, anti-inflammatory therapies have shown limited benefit in idiopathic pulmonary fibrosis, and current antifibrotic drugs slow but rarely reverse disease progression. Moreover, diverse conditions including idiopathic pulmonary fibrosis, post-ARDS or post-infectious fibrosis, radiation-induced injury, drug toxicity, and bronchopulmonary dysplasia arise from distinct causes yet may converge toward shared features of persistent fibrotic remodeling. Here we propose that pulmonary fibrosis represents a self-sustaining pathological tissue-repair state rather than a continuously injury-dependent process. Failure of alveolar epithelial regeneration produces persistent cellular senescence and chronic distress signaling that recruits reparative immune responses. These signals promote fibroblast survival and myofibroblast persistence, leading to extracellular matrix deposition and progressive tissue stiffening. Increased matrix stiffness further disrupts epithelial recovery through mechanotransduction pathways, creating a feedback loop linking epithelial dysfunction, immune mis-repair, stromal stabilization, and mechanical reinforcement. Within this framework, fibrosis persists because the lung behaves as a chronically unhealed wound. This model may help explain disease progression and heterogeneity and suggests that effective therapies must restore epithelial regeneration and disrupt system-level feedback rather than target single profibrotic pathways.

As the roles of poly-ADP-ribose polymerase 7 (PARP7) in tumor immune evasion become increasingly well defined, PARP7 inhibitors have emerged as a promising class of anticancer therapeutics. To date, phase I clinical trials of PARP7 inhibitors have reported no significant cardiovascular adverse events. However, PARP7's involvement in doxorubicin (DOX)-induced cardiotoxicity (DIC), a major clinical limitation of widely used chemotherapeutics, remains poorly understood. Elucidating the functional role of PARP7 in this pathological context is essential for evaluating the therapeutic safety of pharmacological PARP7 inhibition. This study aimed to define the functional role and molecular mechanism of PARP7 in DIC. We demonstrate that PARP7 is robustly and selectively upregulated in cardiomyocytes following DOX exposure. Genetic ablation of PARP7 markedly attenuates DIC. Mechanistically, we identify glutathione peroxidase 4 (GPX4) as a direct ADP-ribosylation substrate of PARP7. PARP7 catalyzes mono-ADP-ribosylation of GPX4, leading to its loss of enzymatic activity. In addition, this suppression of GPX4 is both necessary and sufficient for PARP7-driven ferroptosis in cardiomyocytes. Importantly, cardiomyocyte-specific PARP7 knockdown, achieved via AAV9-cTNT-mediated delivery of short hairpin RNA, effectively reverses established DIC, confirming its therapeutic relevance in clinical translation. Collectively, these findings establish PARP7 as a druggable, cardiomyocyte- specific regulator of ferroptosis and define the PARP7-GPX4 axis as a mechanistically grounded, therapeutically targetable pathway in cardio-oncology.

Lung cancer remains a major global health burden. Although low-dose CT (LDCT) is effective for early detection, its clinical application is limited by a high false-positive rate and the need for subsequent invasive confirmation, such as biopsy. Meanwhile, the extensive protein-level alterations observed in lung cancer provide a rationale for developing minimally invasive plasma proteomics-based screening a panel of biomarkers. In this study, untargeted proteomic profiling was performed on a tissue cohort (n = 61, paired tumor and normal adjacent tissue samples spanning pre-invasive (AAH/AIS), MIA and IAC), a discovery plasma cohort (n = 221), and an independent validation plasma cohort (n = 144). Integrative tissue-plasma analysis was used to identify concordant proteins. Classifier training was conducted on the plasma proteomics data through a LightGBM-based pipeline with a two-stage feature selection strategy to derive plasma protein panels and construct binary classifiers that distinguish malignant from benign nodules. The diagnostic performance of the trained models was then evaluated in an independent validation cohort. Furthermore, binary classifiers were constructed to discriminate the invasiveness of lesions among LUADs. A subset of proteins was identified whose expression in both tissue and plasma was significantly associated with tumor invasiveness. The compact pipeline identified reproducible plasma protein panels and trained LightGBM classifiers that robustly discriminated malignant from benign pulmonary nodules. The classifiers maintained strong performance in the independent validation cohort (AUC-ROC: 0.949-0.986). We developed separate classification models to stratify lung adenocarcinoma subtypes by distinct patterns of invasiveness (AUC-ROC: 0.762-0.803). High-depth proteomics combined with LightGBM enables the identification of robust plasma protein panels for discriminating pulmonary nodules and stratifying invasiveness. This generalizable strategy, along with reproducible biomarker panels, supports non-invasive early diagnosis of lung adenocarcinoma.

Vasculogenic mimicry (VM), wherein tumor cells form vessel-like structures independent of endothelial cells, drives metastasis and therapeutic resistance. Current in vitro VM research relies on conventional two-dimensional imaging, which fails to capture complex three-dimensional VM architecture, limiting anti-VM therapeutic development. We established a novel dynamic 3D imaging platform utilizing light sheet fluorescence microscopy for real-time visualization of physiologically relevant VM structures. Non-small cell lung cancer cell lines with different EGFR mutation statuses were cultured in three-dimensional matrices and monitored continuously. Structural characteristics including tubule diameter, lumen formation, and network complexity were quantified. Following validation of physiological 3D VM formation, we developed a high-content screening platform to assess anti-VM therapeutics, including foslinanib and osimertinib, individually and in combination. Our 3D VM platform revealed patent tubules and hollow lumens (25-50 μm diameter) approximating physiological 3D VM architecture, fundamentally distinct from planar network patterns seen with conventional 2D images. EGFR-mutant cells consistently formed complex 3D VM structures with functional lumens, whereas wild-type cell lines examined did not develop comparable three-dimensional architecture. In an EGFR L858R model, the foslinanib-osimertinib combination produced synergistic disruption of 3D VM structures; in other EGFR-mutant lines, the combination showed additive rather than synergistic effects. These findings indicate that combination activity is context-dependent and linked to specific EGFR genotypes. This 3D imaging platform provides a physiologically relevant, quantitative method for studying VM and screening anti-VM therapeutics, addressing a key limitation of conventional 2D assays. The association between EGFR mutation status and 3D VM formation offers insight into resistance mechanisms and identifies candidate combination strategies for further investigation, including the potential contribution of co-occurring genetic alterations. As a preclinical, hypothesis-generating study, these findings warrant validation in vivo and in clinical settings.