Molecular biomedicine最新文献

Early detection of lung adenocarcinoma (LUAD) remains a major clinical challenge despite the widespread application of low-dose computed tomography (LDCT). Circulating PIWI-interacting RNAs (piRNAs), characterized by tumor-specific expression and high stability, offer promise as non-invasive biomarkers. To improve the diagnostic precision of LDCT screening, we performed a large multi-center study integrating paired tissue-serum omics profiling with machine learning-based biomarker discovery. From 1,521 serum samples (1,033 LUAD, 89 benign pulmonary nodules, and 399 healthy controls), two tumor-derived PIWI-interacting RNAs (piR-hsa-8393202 and piR-hsa-8429916) were identified as highly stable, LUAD-specific molecules closely associated with disease progression. A 2-piRNA diagnostic signature demonstrated robust performance for early-stage LUAD (training AUC = 0.918; validation AUC = 0.863) and adenocarcinoma in situ (training AUC = 0.902; validation AUC = 0.907). Notably, when applied to LDCT-detected indeterminate pulmonary nodules, this signature significantly improved malignant nodule identification (AUC = 0.883), outperforming conventional serum biomarkers such as carcinoembryonic antigen and cytokeratin 19 fragment antigen 21-1. Functional assays further revealed that these piRNAs promote tumor cell proliferation and suppress apoptosis, supporting their oncogenic activity. Collectively, this study establishes circulating piRNAs as non-invasive and mechanistically relevant biomarkers for molecular stratification of pulmonary nodules within LDCT screening programs, providing a clinically applicable tool to refine early lung cancer diagnosis and guide individualized management.

Benign prostatic hyperplasia (BPH) is a prevalent condition characterized by nonmalignant proliferation of epithelial and stromal components in the prostate, frequently resulting in lower urinary tract symptoms in aging men. While receptor tyrosine kinase (RTK) signaling has been implicated in both benign proliferative disorders and malignant tumors, its role in BPH remains insufficiently defined. In this study, transcriptomic analyses of bulk and single-cell RNA sequencing data revealed consistent activation of RTK signaling in prostatic epithelial cells from BPH tissues. Pharmacological inhibition of this pathway using sunitinib suppressed epithelial proliferation in BPH cell lines, organoid models, and an androgen-induced BPH mouse model. Through target screening, colony-stimulating factor 1 receptor (CSF1R) was identified as a central mediator within the RTK signaling cascade. Functional experiments demonstrated that CSF1R promotes epithelial proliferation through activation of the PI3K/AKT/mTOR pathway. Mechanistic studies further showed that fibroblasts, which are expanded in BPH tissues, secrete CSF1 and IL34, both ligands of CSF1R, thereby enhancing downstream signaling and stimulating epithelial growth. Neutralization of these ligands or silencing of CSF1R reversed fibroblast-induced epithelial proliferation and clonogenicity. Clinical observations in patients treated with sunitinib confirmed a significant reduction in prostate volume and improvement in BPH-related urinary symptoms. Collectively, these findings establish a fibroblast/CSF1R/RTK signaling axis that contributes to BPH pathogenesis and support the potential of RTK inhibition as a therapeutic strategy.

The deubiquitinase ubiquitin-specific protease 13 (USP13) has been implicated in various cancers, yet its precise molecular function and clinical significance in colorectal cancer (CRC) remain poorly defined. Here, we identify USP13 as a critical regulator of CRC progression through systematic investigation of its impact on oncogenic signaling pathways. Using luciferase-based pathway screening, we discovered that USP13 activates the mitogen-activated protein kinase (MAPK) signaling cascade. USP13 directly interacts with and stabilizes mitogen-activated protein kinase kinase 3 (MKK3), a key upstream kinase of the p38/MAPK pathway, through removal of K48-linked ubiquitination at the K32 residue. This deubiquitination process requires the UBA domain of USP13 and prevents proteasomal degradation of MKK3, leading to enhanced p38 phosphorylation and activation. Functional validation demonstrated that USP13 and MKK3 significantly promotes CRC cell proliferation, migration, and invasion in vitro. Importantly, in vivo xenograft experiments confirmed that USP13-driven tumor growth depends on MKK3 and can be rescued by constitutive p38 activation. Clinical correlation analysis of CRC patient specimens revealed a strong positive correlation between USP13 and MKK3 expression levels, with elevated USP13 expression associated with advanced disease stage. Our findings not only establish the USP13-MKK3-p38 axis as a crucial molecular pathway in CRC progression but also identify USP13 as a promising therapeutic target.

Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile toward a synthetic phenotype plays a critical role in atherosclerosis. Although the redox-sensitive sentrin/Small Ubiquitin-like Modifier (SUMO)-specific protease 3 (SENP3), which preferentially deconjugates SUMO2/3, has been linked to oxidative stress, its role in atherosclerosis remains poorly defined. In this study, we demonstrate that SENP3 is significantly upregulated in human and mouse atherosclerotic lesions and in VSMCs exposed to pro-atherogenic stimuli. Using smooth muscle-specific Senp3 knockout mice (ApoE^-/-;Senp3^flox/flox;Tagln-Cre) and SENP3-knockdown VSMC models, we show that SENP3 deficiency preserves the contractile phenotype of VSMCs, suppresses their proliferation and migration, and attenuates atherosclerotic lesion development. Specifically, Senp3 deletion reduces plaque formation and lipid accumulation, while enhancing collagen deposition and fibrous cap stability, shifting plaques toward a more stable phenotype. Mechanistically, we determined the transcription factor Krüppel-like factor 4 (KLF4) as a direct substrate of SENP3. SENP3 deSUMOylates KLF4 at lysine 278, thereby inhibiting its ubiquitin-mediated degradation and increasing its stability. We further show that SUMOylation at K278 serves as an intrinsic brake on KLF4-mediated phenotypic switching in VSMCs. These findings reveal that SENP3-driven deSUMOylation of KLF4 regulates VSMC phenotypic switching in atherosclerosis, highlighting the SENP3/KLF4 axis as a pivotal regulator of vascular plasticity and a promising therapeutic target for atherosclerotic disease.

Acne vulgaris is a common chronic inflammatory skin disorder with significant clinical and societal impacts. Severe acne (SA), in particular, causes scarring, disfigurement, and psychosocial distress. The underlying pathogenesis of SA remains poorly understood, hindering the development of effective treatments. In our study, single-cell RNA sequencing (scRNA-seq) of samples from SA, acne, and normal skin was performed, 12 clusters were identified from the total cell population, and macrophages were considered as important cell clusters since all gene modules showed high gene activity for macrophages in the scRNA weighted correlation network analysis (WGCNA). By integrating macrophage-specific differentially expressed genes (DEGs) with Mendelian randomization (MR) analysis, it was found that T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) was identified as a potential immune checkpoint involved in the development of SA. Multiplex immunohistochemistry (mIHC) revealed a decreased tendency for TIM3⁺ neutrophils, an increased presence of TIM3⁺ macrophages (especially TIM3⁺ M2 macrophages), and a reduced population of TIM3⁺ keratinocytes in SA tissues compared to controls. In human immortalized keratinocytes (HaCaT) cells, TIM3 knockdown led to the upregulation of Propionibacterium acnes (P. acnes)-induced proinflammatory cytokine secretion, and the administration of an anti-Tim3 antibody in P.acnes induced mouse model exacerbated acne-associated inflammation. Collectively, these findings support a role for TIM3 in SA and suggest TIM3 as a potential therapeutic target, while underscoring the immunomodulatory function of keratinocytes and providing directions for future investigations.

The long-chain acyl-CoA synthetase (ACSL) family comprises key enzymes that are integral to the fatty acid metabolic pathway and play crucial roles in governing fatty acid (FA) metabolism and lipid homeostasis. These enzymes are involved in multiple pathophysiological processes, including cellular metabolism, endoplasmic reticulum stress, lipid peroxidation, and ferroptosis (iron-dependent cell death). The ACSL family consists of five isoforms-ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6-each of which has been implicated in the pathogenesis, treatment, and prognosis of diverse conditions, including metabolic disorders, cancers, cardiovascular and cerebrovascular diseases, and other clinical conditions. By catalyzing the conversion of polyunsaturated fatty acids into fatty acyl-CoA, these enzymes mediate a range of biological activities, including anti-inflammatory, antioxidant, and antitumor responses, as well as the regulation of ferroptosis through lipid metabolism. Over the past five years, however, there has been a notable lack of comprehensive reviews that systematically summarize the relevance of ACSL to clinical diseases and their underlying molecular mechanisms. The present review seeks to fill this gap by summarizing recent advances in understanding the roles of the ACSL family across diverse diseases, with a focus on emerging therapeutic strategies that target these enzymes. This work provides critical insights that may inform future preclinical and clinical investigations of the ACSL family.