Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact sites between the endoplasmic reticulum (ER) and mitochondria that coordinate multiple cellular processes such as calcium signaling, lipid trafficking, and redox homeostasis. Increasing evidence shows that cancer cells remodel MAMs to support metabolic adaptation, stress tolerance, tumor progression, and therapeutic resistance. In this review, we summarize the structural organization of MAMs, the core tethering and regulatory mechanisms governing their plasticity, and emerging evidence linking MAM dysfunction to malignant phenotypes and therapeutic resistance. We highlight that the roles of MAM-associated proteins in cancer are highly context-dependent, varying with tumor type, metabolic state, and therapeutic pressure. We further discuss emerging therapeutic strategies targeting MAM-associated pathways, as well as combination approaches to overcome resistance. A better mechanistic understanding of MAM remodeling may reveal actionable vulnerabilities and support biomarker-guided precision therapy across cancer types.

Abstract Both tumor-associated macrophage (TAM) and tumor stiffness may support immunosuppression and limit immunotherapy response, particularly in non-small cell lung cancer (NSCLC). TAMs influence extracellular matrix (ECM) remodeling, but whether they also affect tumor stiffness, or are regulated by mechanical signals in turn, remains to be investigated. Here, we use single-cell transcriptomics of primary NSCLC samples to show that TAMs are associated with an immunosuppressive niche and are also a major source of the ECM component fibronectin (FN1). Mechanistically, macrophage-specific FN1 deficiency induces pro-inflammatory macrophages in a subcutaneous tumor mouse model, reduces ECM stiffness, increases lymphocyte infiltration into tumors, strengthens antitumor immunity, and enhances immune checkpoint blockade efficacy. Within TAMs, FN1-mediated cytoskeleton assembly and autophagy induction impair macrophage glycolysis by inhibiting the RAC1-mTOR axis, thereby limiting the antitumor activity of macrophages. Collectively, these findings highlight macrophage-derived FN1 as a mechanical cue for aggravating immunosuppression and as an intervention target to supplement immunotherapy in NSCLC.

Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, and metabolic remodeling is increasingly recognized as a key factor of disease progression. Beyond fatty acids and glucose, branched-chain amino acid (BCAA) metabolism-particularly valine-has emerged as an important regulator of cardiac energetics and mitochondrial function and is strongly associated with adverse cardiovascular outcomes. However, the mechanisms linking valine dysregulation to CVD and its translational relevance remain incompletely understood. Therefore, this review synthesizes current advancements in elucidating metabolic reprogramming in CVD, specifically focusing on valine metabolism. Herein, we discuss the mechanisms by which dysregulated valine catabolism and its bioactive intermediates-including 3-hydroxyisobutyrate and branched-chain α-ketoacids-promote mitochondrial dysfunction, lipid remodeling, inflammation, and thrombotic susceptibility. By incorporating evidence from clinical studies, experimental models, and systems-level analyses, we underscore the central role of valine metabolism in cardiac dysfunction and disease progression. Finally, we evaluate emerging therapeutic strategies targeting valine metabolic pathways, including dietary modulation and enzyme-based interventions, and outline major challenges that must be addressed to translate these approaches into clinical practice. Overall, this review examines the emerging evidence positioning valine metabolism as a potential metabolic hub connecting mitochondrial dysfunction with cardiovascular pathology, while acknowledging that causality remains incompletely established and that valine also serves essential physiological functions. Moreover, this review also underlines its potential as a target for precision diagnostics and metabolic therapy in CVD.

Subarachnoid hemorrhage (SAH) refers to the rupture of intracranial blood vessels, leading to blood entering the subarachnoid space. It is primarily caused by the rupture of intracranial aneurysms and represents a severe acute cerebrovascular disease. Early brain injury (EBI) denotes the pathological changes occurring within 72 h after SAH, including increased intracranial pressure, reduced cerebral blood flow, blood-brain barrier disruption, brain edema, oxidative stress, and neuroinflammation. Ferroptosis is an iron-dependent form of programmed cell death (PCD), and its mechanisms can be summarized into three interrelated aspects: iron metabolism, lipid peroxidation metabolism, and glutathione and amino acid metabolism. Recent studies indicate that ferroptosis is associated with EBI and is significantly correlated with a poor prognosis. This article reviews the latest research progress on ferroptosis in early brain injury after subarachnoid hemorrhage and provides new insights for future research.

Abstract Topic Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies Background Esophageal squamous cell carcinoma (ESCC) with synchronous primary cancers in pharynx and larynx (SPC-PL) is rare and lacks standard-of-care treatment. This study examined tumor response and survival after neoadjuvant immuno-chemotherapy (nICT) in ESCC patients with SPC-PL. Methods This retrospective single-center study analyzed 21 patients with ESCC and SPC-PL who received nICT between 2020 and 2024. Treatment response was evaluated using clinical (endoscopic and radiological) and pathological criteria. Outcomes included response rates, overall survival (OS), and progression-free survival (PFS) and laryngeal preservation rates. Results The nICT regimen induced a clinical complete response (CR) in 71.4% (15/21) of SPC-PL lesions and a pathological CR in 38.5% (5/13) of resected esophageal specimens. With a median follow-up of 28.2 months, the 2-year OS and PFS rates were 75.9% and 44.1%, respectively. Laryngeal-preserving strategies were successfully implemented in 85.7% (6/7) of patients with locally advanced SPC-PL (cT2-3N0-2) who were conventional candidates for total laryngo-pharyngectomy. No significant difference in OS or PFS was observed compared to a concurrent surgical resection cohort (n=18). Conclusion nICT showed promising efficacy in treating ESCC patients with SPC-PL, providing high rates of tumor regression and laryngeal preservation. These results support nICT as an initial treatment option for ESCC patients with SPC-PL but further validation is needed.

4086 Background: Definitive concurrent chemoradiotherapy (dCRT) is the standard treatment for cervical esophageal squamous cell carcinoma (CESCC). However, when dCRT fails, salvage esophagectomy is technically challenging. Moreover, optimizing patient selection for dCRT remains an unresolved concern. We propose a stratified screening strategy by incorporating induction immunochemotherapy, aiming to identify suitable candidates for organ-sparing dCRT and timely surgical treatment. Methods: This prospective interventional phase II study (SCENIC, ChiCTR2200057732) enrolled patients with clinical stage T 2-4 N any M0 (AJCC TNM 8th) resectable CESCC. Eligible participants received induction therapy (IT) of intravenous PD-1 inhibitor tislelizumab (200mg, day 1) plus nab-paclitaxel (100 mg/m 2 , day 1,8,15) and carboplatin (area under curve of 5 mg/mL/min, day 1), administered over two 3-week cycles. Four weeks after IT, treatment response was evaluated via endoscopy and PET-CT. Patients were then divided into 3 groups: remarkable response (RR); limited partial response (LPR); and poor response (POR). RR patients received dCRT, while LPR and POR patients underwent radical surgery. Tislelizumab was maintained after dCRT in RR patients, and postoperative adjuvant therapy was dependent on the patient’s condition, including chemotherapy, radiotherapy, immunotherapy, or follow-up. The primary endpoint is 2-year event-free survival (EFS). Results: From Jul 2022 to Sep 2024, 42 patients were enrolled, with 40 completing two-cycle IT and response evaluation. Post-IT responses were RR in 62.5% (25/40), LPR in 25.0% (10/40), and POR in 12.5% (5/40). All RR patients received subsequent dCRT. In 11 non-RR patients,7 underwent total phryngo-laryngo-esophagectomy(TPLE), 4 received dCRT. Overall, 40 patients (96.0%) had any-grade treatment-related adverse events with leukocytopenia being most prevalent. 5 patients (12.5%) had adverse events of grade 3 or worse. With a median follow-up of 22.3 months (range, 4.5-40.9 months), 2-years EFS rate and overall survival (OS) rate in ITT population was 60.9% and 76.6%. 2-years EFS rate and OS rate in RR group and non-RR group is 78.8% vs 28.0%(p = 0.0011) and 84.8% vs 70.1%(p = 0.0703), respectively. Conclusions: The 2-year survival of RR patients with dCRT followed by IT appears promising compared to historical data. This stratified strategy of induction immunochemotherapy is effective in identifying candidates suitable for dCRT in patients with resectable CESCC. Clinical trial information: ChiCTR2200057732.

Residing at the outermost layer of the skin, the epidermis is composed of stratified squamous epithelial cells. Regular renewal of the epidermis is essential for maintaining its barrier function, which is dependent on the orchestrated proliferation and differentiation of stem cells located in the basal epidermis. This process necessitates precise dual regulation through the intrinsic control of cell division orientation and external microenvironmental influences. In this comprehensive review, we delve into the critical processes underlying epidermis renewal, emphasizing the balance between symmetric and asymmetric cell fate and the integration of differentiated cells into the suprabasal layer. Our paper highlights the pivotal roles of single-cell omics, live imaging, and artificial intelligence (AI)-driven modeling techniques in elucidating the molecular mechanisms governing cell proliferation and differentiation during epidermis renewal.

Zinc finger protein 24 (ZNF24) is a conserved multifunctional transcription factor associated with tumorigenesis, but its function in bladder carcinogenesis remains unclear. Herein, the expression of ZNF24 was decreased in bladder cancer (BC) cells and tissues, and patients with higher expression of ZNF24 had a better prognosis. Doxycycline-induced overexpression and knockdown of ZNF24 identified its anti-proliferative and anti-metastasis role in BC in vitro and in vivo. The potential genes for the anti-cancer role of ZNF24, involving transcriptional regulation of several factors, such as dual-specificity phosphatase 1 and squalene epoxidase. E2 conjugating enzyme UBC9 and small ubiquitin-like modifier (SUMO) 1 were found to interact with ZNF24, suggesting that ZNF24 may be SUMOylated. Consistent with the expression, ZNF24 SUMOylation levels were decreased in BC cells and tissues. Pan-SUMOylation inhibition promoted protein degradation of ZNF24. UBC9 SUMOylated ZNF24 at Lys-27 (K27) site with SUMO1 modification and the K27 mutation of ZNF24 greatly damaged the protein stability of ZNF24. Cullin 3 (CUL3), a E3 ubiquitin ligase, was responsible for the degradation of ZNF24. ZNF24 SUMOylation prevented CUL3-mediated protein degradation of ZNF24. Overall, the crosstalk between the SUMOylation and ubiquitination of ZNF24 may be a novel regulatory mechanism to block tumorigenesis and development of BC.

As the global medical waste continues to rise after COVID-19 pandemic, effective medical waste management (MWM) relying on the Internet of Things (IoT) has become essential in the era of Industry 5.0. Remote temperature and humidity sensing for harsh tank environment face challenges related to wireless smart sensor and IoT data communication. This article aims to develop a wireless dual-parameter inductance capacitance sensor (DPLC-sensor) based on a symmetrical double-resonant circuit and low-power wide-area network (LPWAN) to monitor the risks of tank environment for MWM in real-time. The DPLC-sensor manufactured by low-temperature co-fired ceramic (LTCC) Technology is constructed specifically to prevent physical crosstalk between the two sensor parameters depending on the symmetrical double-resonant circuit. Experimental verification is conducted on a dedicated temperature and humidity test platform. The results indicate that the resonant frequencies for temperature and humidity are entirely independent, demonstrating the sensor's effective sensitivity characteristics. Finally, the performance of LPWAN quality in regards to received signal strength indication (RSSI) and packet receive rate (PDR) for tank environment monitoring is verified. This article is conducted to provide new insights into how a wireless LTCC DPLC-sensor integrating with LPWAN is designed for temperature and humidity sensing accurately for tank environment in MWM and further opening a door for IoT and smart sensor in more MWM scenarios.

HDAC6 is integral to the regulation of primary cilia, which are specialized structures that serve as crucial signaling hubs for cellular communication and environmental response. These ciliary functions are essential for maintaining cellular homeostasis and orchestrating developmental processes. Dysregulation of HDAC6 activity is implicated in ciliopathies, a group of disorders characterized by defective ciliary structure or function, resulting in widespread organ involvement and significant morbidity. This review provides a comprehensive examination of the molecular dynamics of HDAC6 in the context of ciliogenesis and ciliopathies, emphasizing its dual role in the deacetylation of microtubules and regulation of the ciliary axoneme. Furthermore, HDAC6 interacts with key signaling molecules, modulating processes ranging from cell cycle regulation to inflammatory responses, which highlights its central role in cellular physiology and pathology. The therapeutic potential of HDAC6 inhibitors has been explored, with promising results in various disease models, including retinal and renal ciliopathies, highlighting their ability to restore normal ciliary function. This analysis not only underscores the critical importance of HDAC6 in maintaining ciliary integrity but also illustrates how targeting the HDAC6-cilia axis could provide a groundbreaking approach to treating these complex disorders. In doing so, this review sets the stage for future investigations into HDAC6-targeted therapies, potentially transforming the clinical management of ciliopathies and significantly improving patient outcomes.

Esophageal squamous cell carcinoma (ESCC) carries a high risk of recurrence and metastasis and is associated with poor prognosis. Chemotherapy remains essential for ESCC treatment. Oxaliplatin (OXA), a third-generation platinum drug, offers advantages in cancer therapy; however, its lack of tumor targeting and high toxicity to normal cells limit clinical efficacy. To address this, we developed photothermal-assisted nanoparticles coated with N1-type neutrophil membranes engineered to express interleukin-21 (IL-21) on their surface and co-loaded with OXA and BMT-BBT (a photosensitizer) (OXA-BMT@ICVs) to enhance tumor killing. Results demonstrated effective uptake of OXA-BMT@ICVs by ESCC cells (KYSE-150) in vitro. This uptake induced immunogenic cell death (ICD) via activation of oxidative stress and mitochondrial dysfunction, further triggering the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. In vivo studies revealed that, combined with photothermal therapy (PTT), OXA-BMT@ICVs accumulated within tumor tissue, enabling targeted release of OXA and BMT-BBT. The combined action of the cytokine IL-21 and the chemotherapeutic drug activated immune responses, promoting dendritic cell (DC) maturation and CD8+ T cell infiltration. This enhanced inflammatory responses and immune-mediated killing while activating the cGAS-STING pathway, thereby inducing ICD. The combination of OXA-BMT@ICVs and PTT significantly inhibited tumor cell proliferation, promoted apoptosis, and suppressed tumor growth in ESCC-bearing mice. This strategy activates potent immune responses, reduces systemic toxicity, exhibits good biocompatibility and safety, and represents a promising approach for ESCC clinical treatment.

Glycosylation is a highly dynamic and complex post-translational modification that plays a pivotal role in regulating protein folding, trafficking, stability, and function. Accumulating evidence indicates that aberrant glycosylation is intimately involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review provides a comprehensive overview of the molecular mechanisms by which the two predominant forms of glycosylation, N-glycosylation and O-GlcNAcylation, contribute to protein misfolding, synaptic dysfunction, neuroinflammation, and impaired stress responses in the diseased nervous system. We further explore the diagnostic potential of glycosylation biomarkers and emerging therapeutic strategies targeting glycosylation pathways. Special emphasis has been placed on recent advances in glycomic technologies, artificial intelligence-driven analytics, and nanocarrier-based drug delivery platforms. By integrating mechanistic insights with translational applications, this review highlights glycosylation as both a pathological driver and a promising therapeutic target in neurodegenerative disorders.

Roles of primary cilia and the signals they transmit in the development of myocardial fibrogenesis, cardiac hypertrophy, and atrial fibrillation. Left, Fibroblasts can differentiate into myofibroblasts in response to TGF-β1. TGF-β1 stimulation via both paracrine action in the heart and exogenous action on primary cultured fibroblasts activated the phosphorylation of SMAD3 and the transcription of the fibronectin and collagen type I and III genes. Middle, Vesicles derived from cilia are secreted at an accelerated rate under fluid shear stress. Blockage of ciliary protein, which is required for cELV generation with shRNA, led to blunted cELV secretion and left ventricular hypertrophy. Right, under pathological conditions such as atrial fibrillation (AF), fibroblasts exhibit increased proliferation and differentiation into α-smooth muscle Actin (αSMA)-expressing myofibroblasts. This disrupts ECM dynamics, ultimately leading to interstitial fibrosis within the atria. AF patients presented increased HDAC6 activity and reduced levels of acetylated α-tubulin in left atrial tissues. HDAC6 activity is activated by the interaction of aurora kinase A (AURKA), and neural precursor cells express developmentally downregulated protein 9 (NEDD9) via phosphorylation. LiCl prompts the reversion of αSMA-positive myofibroblasts into αSMA-negative fibroblasts.

Pure solid lung cancer is associated with higher lymph node metastasis rates, therefore identifying the risk factors and metastatic patterns of lymph node involvement in early-stage pure solid lung cancer is a critical research topic. We retrospectively collected preoperative Computed Tomography (CT) imaging and postoperative pathological data of patients with pure solid lung cancer from 2021 to 2025 to investigate the risk factors and patterns of lymph node metastasis. Among 8718 patients, 104 with ≤ 2 cm pure solid lung cancer were analyzed, with a lymph node metastasis rate of 20.19

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with similar to 50 million people experiencing TBI each year. Ferroptosis, a form of regulated cell death triggered by iron ion-catalyzed and reactive oxygen species-induced lipid peroxidation, has been identified as a potential contributor to traumatic central nervous system conditions, suggesting its involvement in the pathogenesis of TBI. Alterations in iron metabolism play a crucial role in secondary injury following TBI. This study aimed to explore the role of ferroptosis in TBI, focusing on iron metabolism disorders, lipid metabolism disorders and the regulatory axis of system Xc(-)/glutathione/glutathione peroxidase 4 in TBI. Additionally, we examined the involvement of ferroptosis in the chronic TBI stage. Based on these findings, we discuss potential therapeutic interventions targeting ferroptosis after TBI. In conclusion, this review provides novel insights into the pathology of TBI and proposes potential therapeutic targets.