Background: Gastrointestinal cancers remain a leading cause of cancer-related morbidity and mortality worldwide, with surgery being central to curative treatment. Tumour-targeted fluorescence-guided surgery (tFGS) has emerged as a promising approach to improve intraoperative visualisation and oncological precision.
Methods: We conducted a systematic review of preclinical and clinical studies on tFGS in gastrointestinal oncology, registered in PROSPERO (ID: 558994) and following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches of PubMed and Embase identified 133 eligible studies.
Results: Nine tracers have currently been evaluated in clinical trials, targeting the following biomarkers: carcinoembryonic antigen, vascular endothelial growth factor, epidermal growth factor receptor, folate receptor α and/or β, integrin αvβ3, 5-aminolevulinic acid and acidic tumour microenvironment. Clinical trials demonstrated that tracers like SGM-101 and panitumumab-IRDye800CW can achieve high tumour-to-background ratios (TBRs) up to 6.1 ex vivo and alter surgical strategy in up to 35% of cases. Preclinical research identified additional promising targets, including mucins, epithelial cell adhesion molecules, urokinase receptors, tumour-associated glycoproteins, gamma-glutamyl transferase, organic anion transporting polypeptides, human epidermal growth factors 1/2 and Lewis antibodies, with TBRs frequently exceeding three. Despite encouraging feasibility and safety data, translation into routine practice is hampered. Confirmation from early health technology assessments is needed to advance tFGS. Besides, standardisation of protocols and phase III confirmatory trials are required to establish clinical benefit and support regulatory approval.
Conclusion: tFGS holds considerable potential to transform surgical oncology in GI cancers by enabling more precise resections and guiding organ-preserving strategies. Future innovations in multimodal tracers, NIR-II fluorophores and theranostics may further enhance the precision and therapeutic potential of tFGS.
Key points: Tumour-targeted fluorescence-guided surgery (Ttfgs) enhances intraoperative precision in gastrointestinal cancer treatment. Translation of (Ttfgs) into clinical practice is limited by heterogeneity, regulatory hurdles, biomarker variability and absence of phase III trials. Innovations such as multimodal tracers and theranostic agents may further enhance the precision and therapeutic potential of Ttfgs.
Background: Short stature (SS) is a common growth disorder with multiple aetiologies. Variants in the MMP13 gene can result in varying degrees of SS, typically accompanied by pronounced skeletal abnormalities. This study aimed to investigate the genetic basis of SS in a family lacking significant imaging abnormalities and elucidate the underlying pathogenic mechanism.
Methods: Trio whole-exome sequencing was performed in a Chinese pedigree with SS to identify pathogenic variants, followed by Sanger sequencing validation. Patient-derived induced pluripotent stem cell model and CRISPR/Cas9-generated Mmp13R459fs homologous mutant mouse model were established to verify the pathogenicity of the variant. Western blotting, immunofluorescence staining, co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), histological staining and transmission electron microscopy were used to evaluate the effects of the variant on MMP13 protein function and chondrocyte development.
Results: A heterozygous frameshift variant, NM_002427.4:c.1372del(p.Arg458Valfs*31), was identified in the MMP13 gene. Mmp13R459fs mutant mice recapitulated the SS phenotype in patients, with growth plate abnormalities that were present only during the growth phase and resolved earlier than those in Mmp13 knockout mice. Co-IP/MS in HEK293T cells revealed significantly increased HSPA5 expression in the mutant, and enhanced interaction between MMP13 mutant and HSPA5 was confirmed, leading to their retention within the endoplasmic reticulum (ER). In patient-derived chondrocytes, misfolded MMP13 protein upregulated HSPA5 expression, induced significant ER dilation, activated unfolded protein response and increased chondrocyte apoptosis, ultimately contributing to MMP13-related SS.
Conclusion: This study for the first time reports the MMP13 c.1372del (p.Arg458Valfs*31) variant causes autosomal dominant SS without obvious skeletal abnormalities. The variant is associated with defective MMP13 protein secretion and ER stress. These findings expand the mutational spectrum and genotype‒phenotype correlations of the MMP13 gene, providing a novel pathogenic mechanism of SS that is important for the precise diagnosis and treatment.
Key points: The MMP13 R458fs variant is retained in the endoplasmic reticulum (ER), leading to ER expansion. Enhanced binding of variant MMP13 to HSPA5 triggers ER stress, thereby increasing chondrocyte apoptosis. This pathogenic cascade results in abnormal expansion of the growth plate hypertrophic zone, ultimately impairing long bone growth and causing short stature.
Background: Metabolic reprogramming is a key cancer hallmark, with dysregulated fatty acid metabolism critical for tumorigenesis and progression. The acyl-CoA synthetase long-chain (ACSL) family (ACSL1-ACSL6) catalyzes ATP-dependent activation of long-chain fatty acids into acyl-CoA, a bioactive intermediate in lipid synthesis, β-oxidation, membrane biogenesis, and signal transduction. Dysregulated ACSL expression is widespread in malignancies, but their non-metabolic functions (ferroptosis regulation, tumor immune microenvironment remodeling) and translational potential of targeted therapies remain to be systematically summarized.
Methods: This narrative review comprehensively synthesizes existing literature on the biological functions of ACSL family members in cancer. We retrieved and analyzed studies focusing on ACSL-mediated lipid metabolic reprogramming, ferroptosis modulation, and immunomodulatory effects, with particular emphasis on isoform-specific mechanisms and the context-dependent roles (pro-tumorigenic or tumor-suppressive) of the ACSL family across different cancer types. Additionally, we summarized emerging therapeutic strategies targeting ACSL isoforms and their translational potential.
Results: ACSL isoforms exert distinct context-dependent effects:ACSL1 promotes immunosuppressive TIME via M2 macrophage polarization;ACSL3/4 have antagonistic roles in ferroptosis;ACSL5 exerts dual effects via lipid metabolism, apoptosis, and immunity;ACSL6 involves autophagy and hematological malignancies. Dysregulation correlates with tumor progression, drug resistance, and immunotherapy response, while emerging ACSL-targeted drugs show substantial translational potential.
Conclusions: The ACSL family serves as a key regulatory node integrating lipid metabolism, ferroptosis, and tumor immunity. Its isoform-specific mechanisms and context-dependent characteristics highlight its potential as a precise therapeutic target. Future research should focus on optimizing isoform-selective inhibitors, clarifying their synergistic effects with existing therapies (e.g., immune checkpoint inhibitors, radiotherapy), and validating their translational efficacy through clinical trials to advance the development of innovative cancer treatment strategies.
Introduction: Patients undergoing multiple wound repair surgeries often develop moderate-to-severe anxiety and depression. However, there is a lack of effective rapid emotional intervention strategies during the perioperative period.
Methods: This multi-centre, randomized, double-blind, placebo-controlled trial involved 130 adult patients (65 in the esketamine group and 65 in the placebo group). Participants were randomly assigned to receive either esketamine (0.2-0.3 mg/kg) or saline intravenously during surgery. The primary outcome was the response rate (proportion of patients with ≥50% reduction in MADRS total score from baseline) on postoperative days (PODs) 1-3, evaluated using the Montgomery-Åsberg depression rating scale (MADRS). The secondary outcome was the remission rate (proportion of patients with MADRS total score ≤10) on postoperative days (PODs) 1-3; scores on the Patient Health Questionnaire-9 (PHQ-9), the Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A); and esketamine-related neuropsychiatric adverse events assessed using the Young Mania Rating Scale (YMRS), Clinician-Administered Dissociative States Scale (CADSS), and Brief Psychiatric Rating Scale (BPRS) within 30 days after surgery.
Results: The esketamine group showed a significantly higher response rate than the placebo group on POD 1-3. (POD 1: 53.8% vs. 26.2%, p = 0.001; POD 2: 60.0% vs. 40.0%, p = 0.009; POD 3: 73.8% vs. 53.8%, p = 0.018). The esketamine group also showed a higher remission rate and lower MADRS scores (POD 1: 33.8% vs. 10.8%, p = 0.002; POD 2: 40.0% vs. 23.1%, p = 0.038; POD 3: 56.9% vs. 23.1%, p < 0.001). Esketamine improved HADS-A and PHQ-9 scores by POD 3 without increasing neuropsychiatric adverse events within 30 days postoperatively.
Conclusions: The results demonstrate that the intraoperative use of low-dose esketamine can rapidly and effectively alleviate moderate-to-severe anxiety and depressive symptoms in the early postoperative period (POD 1-3) among patients requiring repeated debridement surgeries without increasing neuropsychiatric or systemic adverse events within 30 days after surgery.
Complement is increasingly recognised as a driver and modulator of antitumour immunity, with context-dependent effects across T cells, myeloid subsets, stromal elements and tumour cells. Although best known for pathogen clearance and membrane attack complex (MAC) formation, complement also acts intracellularly via the ‘complosome’ to regulate cellular homeostasis and gene expression. Complosome activity may dampen antitumour responses by rewiring single-cell metabolism and transcription, altering nutrient flux and fostering an immunosuppressive microenvironment. Here, we synthesise advances in intracellular and extracellular complement, with emphasis on complement component 3 (C3) and receptors (C3aR1, C5aR1/CD88, C5aR2/C5L2), highlighting how these pathways shape T-cell metabolism, exhaustion programmes and inflammatory tone within tumours. Evidence indicates that tonic C3/C5 signalling restrains cytotoxicity via C5aR1-driven myeloid recruitment and cytokine cascades, while complosome signalling tunes T-cell activation thresholds and bioenergetics. We outline considerations for selectively modulating intracellular versus extracellular complement, propose cell-type-resolved biomarker strategies and identify opportunities for complosome-directed therapies in cancer, integrating roles across T cells, macrophages, B cells, neutrophils, NK cells, regulatory T cells, dendritic cells, myeloid-derived suppressor cells and cancer-associated fibroblasts.
Colorectal cancer is a leading cause of cancer mortality characterised by a unique metabolic microenvironment and complex interactions with the gut microbiota. Lactylation, a novel post-translational modification derived from lactate, has emerged as a key epigenetic regulator connecting metabolic reprogramming to gene expression. While its general roles in cancer are recognised, the tissue-specific regulatory network of lactylation in colorectal cancer—particularly its interplay with the gut microbiome and specific chemotherapy resistance mechanisms—remains underexplored.
This review systematically dissects the dynamic ‘writer‒eraser‒reader’ network of lactylation, highlighting its distinct oncogenic functions in colorectal cancer. We reveal a critical ‘microbiome‒metabolism‒epigenetics’ axis in which gut flora-derived metabolites (including D-lactate) remodel the tumour microenvironment and drive immune evasion. Beyond histone modifications, we emphasise the pivotal role of non-histone lactylation targets (e.g., eEF1A2, PD-L1) in orchestrating malignant proliferation and promoting liver metastasis by priming the pre-metastatic niche. Furthermore, we elucidate novel mechanisms by which lactylation induces resistance to standard chemotherapeutic agents (5-fluorouracil and oxaliplatin), specifically through the enhancement of DNA repair and the suppression of ferroptosis. We also critically evaluate the pharmacological challenges hindering clinical translation, such as the poor selectivity of current broad-spectrum inhibitors.
Lactylation serves as a fundamental metabolic‒epigenetic link driving aggressive phenotypes in colorectal cancer. By delineating these tissue-specific mechanisms and proposing next-generation site-specific targeting strategies, this review provides a theoretical foundation for developing precision medicine interventions to overcome therapy resistance in colorectal cancer patients.
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