2 regarding the role of KCTD17 in progression of hepatocellular carcinoma (HCC).As the editorial highlights, identifying reliable biomarkers and developing novel therapeutic strategies are urgently needed for HCC, especially given that most patients with HCC are diagnosed at an advanced stage, where therapeutic options are severely limited. 3,4The findings presented in our study are therefore both groundbreaking and significant, as our research not only highlights KCTD17 as a novel diagnostic and prognostic biomarker but also unravels its mechanistic role in the Ras signaling pathway, thereby providing new avenues for therapeutic intervention, and significantly expanding our understanding of the molecular mechanisms underlying HCC progression and potential treatment strategies.While our findings are promising, several important questions remain unanswered, meriting further investigation.As Dr. Leung and Dr. Lee have pointed out, one critical area that requires additional exploration is the potential role of KCTD17 in regulating the specificity of Ras isoforms.Previous studies have demonstrated that leucine zipper-like transcription regulator 1 (Lztr1) promotes the polyubiquitination and degradation of Ras family members by recruiting a Cul3 ubiquitin ligase complex, thereby inhibiting Ras/ MAPK signaling. [5][6]6][7] In our study, we found that KCTD17 interacts with Lztr1, increasing its ubiquitination, which in turn inhibits Lztr1-mediated Ras ubiquitination.Given that Lztr1 functions as a "multiple Ras killer protein" regardless of the Ras isoform involved, 5 and that KCTD17 induces Lztr1 proteasomal degradation, it is plausible that KCTD17 could regulate multiple Ras isoform.Indeed, our study shows that KCTD17 promotes both H-Ras and K-Ras. 2 However, we have not yet investigated the effects of

KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.

2 regarding the role of KCTD17 in progression of hepatocellular carcinoma (HCC).As the editorial highlights, identifying reliable biomarkers and developing novel therapeutic strategies are urgently needed for HCC, especially given that most patients with HCC are diagnosed at an advanced stage, where therapeutic options are severely limited. 3,4The findings presented in our study are therefore both groundbreaking and significant, as our research not only highlights KCTD17 as a novel diagnostic and prognostic biomarker but also unravels its mechanistic role in the Ras signaling pathway, thereby providing new avenues for therapeutic intervention, and significantly expanding our understanding of the molecular mechanisms underlying HCC progression and potential treatment strategies.While our findings are promising, several important questions remain unanswered, meriting further investigation.As Dr. Leung and Dr. Lee have pointed out, one critical area that requires additional exploration is the potential role of KCTD17 in regulating the specificity of Ras isoforms.Previous studies have demonstrated that leucine zipper-like transcription regulator 1 (Lztr1) promotes the polyubiquitination and degradation of Ras family members by recruiting a Cul3 ubiquitin ligase complex, thereby inhibiting Ras/ MAPK signaling. [5][6]6][7] In our study, we found that KCTD17 interacts with Lztr1, increasing its ubiquitination, which in turn inhibits Lztr1-mediated Ras ubiquitination.Given that Lztr1 functions as a "multiple Ras killer protein" regardless of the Ras isoform involved, 5 and that KCTD17 induces Lztr1 proteasomal degradation, it is plausible that KCTD17 could regulate multiple Ras isoform.Indeed, our study shows that KCTD17 promotes both H-Ras and K-Ras. 2 However, we have not yet investigated the effects of

KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.

Nodal follicular helper T-cell (T _FH) lymphoma of the angioimmunoblastic (AITL) subtype has a dismal prognosis. Using whole-exome sequencing (n = 124), transcriptomic (n = 78), and methylation (n = 40) analysis, we identified recurrent mutations in known epigenetic drivers (TET2, DNMT3A, IDH2 ^R172 ) and novel ones (TET3, KMT2D). TET2, IDH2 ^R172 , DNMT3A co-mutated AITLs had poor prognosis (p < 0.0001). Genes regulating T-cell receptor (TCR) signaling (CD28, PLCG1, VAV1, FYN) or activation (RHOA ^G17V ) or regulators of the PI3K-pathway (PIK(3)C members, PTEN, PHLPP1, PHLPP2) were mutated. CD28 mutation/fusion was associated with poor prognosis (p = 0.02). WES of purified, neoplastic T-cell (CD3⁺PD1⁺) demonstrated high concordance with whole tumor biopsies and validated the presence of TET2 and DNMT3A in tumor and non-lymphoid cells, but other mutations (CD28, RHOA ^G17V , IDH2 ^R172 , PLCG1) in neoplastic cells. Integrated DNA-methylation and mRNA expression analysis revealed epigenetic alterations in genes regulating TCR, cytokines, PI3K-signaling, and apoptosis. RNA-seq analysis identified fusion transcripts regulating TCR-activation (8%), revealed a restricted TCR-repertoire (α = 87%, β = 72%), and showed the presence of Epstein-Barr virus transcriptome (73%). GEP demonstrated the association of B-cells or dendritic cells in the tumor milieu with prognosis (p < 0.01). RNA-seq and WES analysis of 12 AITL-patient-derived-xenografts (PDX) showed that bi-allelic TET2 and DNMT3A mutations or sub-clonal mutations (PLCG1, PHLPP2) propagated in sequential passages, and gene signatures related to T _FH and T _CM (central-memory) were well-maintained through passages. Gene expression signatures associated with late PDX passages (3rd-5th) were enriched with proliferation and metabolic reprogramming-related genes and predicted prognosis in an independent AITL series. Low PHLPP2 mRNA expression predicted poor prognosis (p = 0.05) and engineered PHLPP2 or TET2 loss in CD4⁺ T-cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.

Semaglutide has recently received conditional accelerated approval in the US for treatment of metabolic dysfunction-associated steatohepatitis (MASH) with significant or advanced liver fibrosis (stage F2/F3). Phase 2 and 3 clinical trials show that subcutaneous semaglutide 2.4 mg/week leads to significant improvements in hepatic steatosis, disease activity, resolution of MASH and reduction in liver fibrosis. These benefits parallel weight loss and are accompanied by improved metabolic outcomes, including better glucose control and lipid profiles, as well as consistent benefits for cardiovascular and renal health. The treatment's safety profile is manageable, with gastrointestinal issues being the most frequent side effects, and no new safety concerns have been identified. Data on long-term tolerability, treatment retention and clinical events are now awaited in people with MASH fibrosis. The evidence regarding semaglutide's ability to directly target the liver and improve liver damage in cirrhosis, and its impact on muscle mass in at-risk populations, remains limited. Thus, in patients with advanced disease, it should be viewed primarily as a therapy that modifies metabolic disease. Practically, semaglutide is most suitable as a first-line treatment to prevent liver complications for people with MASH and stage F2/F3 fibrosis with severe metabolic dysfunction, obesity, or type 2 diabetes who could benefit from both liver and cardiovascular-renal improvements. Treatment should be tailoured to each individual, with ongoing monitoring of body weight, serum aminotransferase levels and direct measurement of liver fat and stiffness to guide therapy.

PURPOSE: Exercise–microbiome research is expanding rapidly, but methodological heterogeneity and technical limitations still hinder reproducibility and mechanistic interpretation. This review provides a comprehensive methodological roadmap to overcome these barriers.METHODS: We conducted a structured literature search in PubMed, Web of Science, and Scopus for records published between 1998 and 2025 using predefined combinations of exercise and gut-microbiome terms. After deduplication, titles/abstracts and full texts were screened according to prespecified criteria, yielding 99 eligible studies on aerobic and resistance/anaerobic exercise and gut microbiota. Evidence is critically appraised across standard short-read 16S rRNA protocols, shotgun metagenomics, and emerging long-read sequencing, as well as metatranscriptomics, metabolomics, and associated bioinformatics pipelines. A PRISMA-style flow diagram summarizes the study-selection process.RESULTS: Exercise across diverse modalities reshapes gut microbial diversity and community structure, frequently enriching taxa such as &lt;i&gt;Akkermansia muciniphila&lt;/i&gt; and &lt;i&gt;Veillonella&lt;/i&gt; and enhancing production of short-chain fatty acids (SCFAs). SCFAs strengthen the intestinal barrier, activate anti-inflammatory pathways, and supply energy substrates for colonocytes and exercising muscle. Long-read sequencing now enables species- and strain-level resolution beyond short V-region amplicons, while inclusion of the gut mycobiome and virome expands ecological scope. Multi-omics designs integrating metagenomics, metatranscriptomics, and metabolomics connect microbial composition with functional outputs and host metabolic adaptations.CONCLUSIONS: The future of exercise–microbiome science lies not in enlarging static catalogs of responsive microorganisms but in constructing individual-level predictive models. Integrating long-read sequencing and multi-omics with standardized training metadata will enable precision exercise prescriptions and microbiome-targeted interventions, including tailored probiotics, synbiotics, and nutrition strategies. Adoption of these advanced methodologies can accelerate mechanistic insight and promote translation of exercise– microbiome research into athletic performance optimization and clinical practice.

Skin aging is a complex biological process driven by intrinsic and extrinsic factors, leading to a progressive structural and functional decline. The balance between extracellular matrix (ECM) degradation and synthesis is critical for maintaining skin homeostasis, with collagen loss and reduced cell proliferation contributing to age-related deterioration. Serpin Family A Member 3 (SERPINA3), a serine protease inhibitor, has been implicated in inflammation and tissue remodeling. However, its role in skin aging remains largely unexplored. In this study, we examined the expression and function of SERPINA3 in human skin cells. RNA-seq analysis revealed that SERPINA3 expression is significantly downregulated in aged human dermal fibroblasts and was further diminished under oxidative stress. Functional assays demonstrated that SERPINA3 promotes cell proliferation, accelerates wound healing, and activates key signaling pathways such as ERK and AKT. These findings suggest that SERPINA3 may serve as a protective factor against skin aging by supporting ECM integrity and enhancing cellular regeneration. These results provide novel insights into the molecular functions of SERPINA3 and highlight its potential as a therapeutic target for age-related skin deterioration. [BMB Reports 2025; 58(6): 264-268].

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease. Available therapies show inconsistent results on fibrosis, probably due to heterogeneity in disease trajectory or incomplete understanding of molecular determinants. Here we identified increased KCTD17 levels in patients with MASH, and in dietary rodent models of MASH-such as those fed a diet high in palmitate, sucrose and cholesterol coupled with fructose-containing drinking water or a choline-deficient, L-amino acid-defined, high-fat diet-which showed an inverse correlation with the expression of serine protease inhibitor a3k (SERPINA3 in humans, Serpina3k in mice). KCTD17 depletion increased SERPINA3 levels and reduced liver fibrosis in mice fed a MASH-inducing diet by inhibiting Par2/TGFβ-mediated activation of hepatic stellate cells. Mechanistically, Kctd17 regulates Serpina3k expression by facilitating the ubiquitin-mediated degradation of Zbtb7b, which in turn diminishes Serpina3k secretion. Consequently, pharmacological inhibition of Kctd17 effectively reverses MASH-induced liver fibrosis. In summary, these findings underscore the therapeutic potential of targeting KCTD17 for the treatment of MASH-induced liver fibrosis.

The ubiquitin-proteasome system is a vital protein degradation system that is involved in various cellular processes, such as cell cycle progression, apoptosis, and differentiation. Dysregulation of this system has been implicated in numerous diseases, including cancer, vascular disease, and neurodegenerative disorders. Induction of cellular senescence in hepatocellular carcinoma (HCC) is a potential anticancer strategy, but the precise role of the ubiquitin-proteasome system in cellular senescence remains unclear. In this study, we show that the E3 ubiquitin ligase, TRIM22, plays a critical role in the cellular senescence of HCC cells. TRIM22 expression is transcriptionally upregulated by p53 in HCC cells experiencing ionizing radiation (IR)-induced senescence. Overexpression of TRIM22 triggers cellular senescence by targeting the AKT phosphatase, PHLPP2. Mechanistically, the SPRY domain of TRIM22 directly associates with the C-terminal domain of PHLPP2, which contains phosphorylation sites that are subject to IKKβ-mediated phosphorylation. The TRIM22-mediated PHLPP2 degradation leads to activation of AKT-p53-p21 signaling, ultimately resulting in cellular senescence. In both human HCC databases and patient specimens, the levels of TRIM22 and PHLPP2 show inverse correlations at the mRNA and protein levels. Collectively, our findings reveal that TRIM22 regulates cancer cell senescence by modulating the proteasomal degradation of PHLPP2 in HCC cells, suggesting that TRIM22 could potentially serve as a therapeutic target for treating cancer.