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Background Hepatocellular carcinoma (HCC) is a highly prevalent and fatal digestive system malignancy, challenging to treat due to its latent onset and non-specific symptoms in advanced stages. Somatic mutations play a crucial role in hepatocarcinogenesis, with nearly half of HCC patients carrying oncogenic driver mutations such as TP53, CTNNB1, or TERT. In parallel, germline susceptibility variants identified by genome-wide association studies (GWAS) — including loci near TERT, MBOAT7, TM6SF2, and PNPLA3 — reveal inherited predisposition that shapes the molecular landscape for HCC development. Despite recent therapeutic advancements, long-term survival remains suboptimal, necessitating a deeper understanding of its pathogenesis and the identification of precise molecular targets. Traditional genomic studies, such as genome-wide association studies (GWAS), have successfully identified associated variants; however, due to their statistical design, they do not provide direct causal inference, functional supportive analyses, or comprehensive insight into multi-level molecular regulation and tumor microenvironment heterogeneity, serving instead as a critical starting point for subsequent functional and integrative analyses. Methods To address these gaps, this study employed an integrated multi-omics approach combining HCC GWAS summary data (FinnGen) with expression (eQTL from GTEx V8), methylation (mQTL), and protein (pQTL from ARIC, UKBPPP, DECODE) quantitative trait loci data. We utilized Summary-data-based Mendelian Randomization (SMR) to infer causal associations between molecular traits and HCC risk, prioritizing candidates with higher clinical translation potential. To refine SMR-based prioritization of candidate genes, bulk transcriptome sequencing and ELISA-based quantification were performed as complementary analyses on peripheral blood samples from 10 HCC patients and 10 healthy controls. Following SMR-based gene prioritization, bulk transcriptome and spatial transcriptomic analyses were first used to refine candidate selection and guide subsequent quantification, thereby avoiding unnecessary assays and optimizing the use of clinical samples and research resources. These analyses aimed to assess whether expression changes were directionally consistent with eQTL and pQTL effects, providing supportive—rather than confirmatory—evidence for the inferred genetic associations. Spatial transcriptomics was applied to HCC tissue sections to map region-specific expression patterns of candidate genes. Finally, publicly available single-cell RNA sequencing (scRNA-seq) data was analyzed to resolve cell composition changes, cell-type-specific expression, and intercellular communication networks within the HCC tumor microenvironment. Results Multi-omics SMR analysis identified numerous loci causally associated with HCC risk, with eQTL SMR revealing enrichment in critical cancer pathways (“Signal transduction,” “Cancer: overview,” “Immune system”). A robust and replicated causal signal for proteins was found on chromosome 19 across three independent pQTL cohorts, with a secondary signal on chromosome 2. The intersection of mQTL, eQTL, and pQTL SMR analyses yielded a core set of 16 candidate genes. Peripheral blood transcriptome profiling showed a clear separation between HCC and controls, with 13 of these 16 genes (e.g., LY9, ST6GAL1, SHMT1) significantly differentially expressed. ELISA validated elevated protein levels of ST6GAL1, PSMB1, LY9, and JUND, and decreased SOD4 in HCC patients. Spatial transcriptomics revealed significant intra-tumoral heterogeneity and distinct, localized expression patterns for genes like ST6GAL1, LGALS1, and JUND. Single-cell RNA sequencing unveiled shifts in cell type composition (e.g., increased Cytotoxic CD4 + T cells and MDSCs, decreased hepatocytes in tumors), cell-type specific expression of candidate genes, and complex intercellular communication networks. Conclusion By integrating germline (GWAS-based) and somatic evidence, this study provides a comprehensive view of HCC pathogenesis. This integrated strategy successfully identified a core set of genes and proteins with potential causal links to HCC, elucidating their functional convergence in cancer biology. These findings offer novel molecular insights and candidate targets for precise diagnosis, prognostic assessment, and targeted therapy of HCC, laying a solid foundation for future translational research.

Tripterygium glycosides tablets (TGT) are effective against autoimmune diseases but cause significant drug-induced liver injury (DILI) that limits clinical use. While TGT disrupts hepatic iron-lipid homeostasis and co-administration with Total Glucosides of Peony (TGP) mitigates its toxicity, the multi-cellular mechanisms remain unclear. In the current study, using integrative single-cell RNA sequencing and pathological validation in controlled mouse models (TGT vs.Con and TGT + TGP vs. TGT.) we elucidated a pathogenic iron-lipid axis driving hepatotoxicity via cellular cascades. TGT initiated Kupffer cell M1 polarization, releasing pro-inflammatory cytokines (TNF-α and IL-1β) that recruited neutrophils and induced NETosis-mediated oxidative stress. Concurrently, hepatic endothelial cells developed iron overload with increased Hamp and decreased Slc40a1, alongside inflammatory damage, while hepatocytes exhibited fatty acid metabolic dysfunction and lipid peroxidation, collectively propagating adipocyte hyperplasia and perilipin-2-driven lipid accumulation. Critically, TGP rescued toxicity by reversing Kupffer cell M1-to-M2 polarization with decreased iNOS and increased CD206, suppressing NET formation with decreased Ly6G and CitH3, alleviating iron deposition with reduced Prussian blue staining, and normalizing lipid metabolism with decreased oil red O staining and perilipin-2. This study identifies the iron-lipid axis as the central driver of TGT-induced liver injury, which is mediated by a sequential multi-cellular cascade involving Kupffer cells, neutrophils, endothelial cells, hepatocytes, and adipocytes. These findings position TGP as a multi-target detoxification agent that mechanistically disrupts this axis and establishes a cellular hierarchy blueprint for metabolic toxicity intervention, supporting its potential as a rescue strategy for precision medicine and detoxification screening. Graphical abstract

Background Paclitaxel-induced peripheral neuropathy (PIPN) is a challenging clinical problem during chemotherapy. Our previous work found that herbal formula Huangqi Guizhi Wuwu decoction (HGWD) could reduce oxaliplatin-induced neurotoxicity. However, its effect on PIPN remains unknown. In this study, we aim to investigate the therapeutic effect and the underlying mechanisms of HGWD against PIPN with pharmacological experiment and network pharmacology. Methods Male Wistar rats were used to establish an animal model of PIPN and treated with different doses of HGWD for 3 weeks. Mechanical allodynia, thermal hyperalgesia and body weight were measured to evaluate the therapeutic effect of HGWD on PIPN rats. On the day of the sacrifice, blood, DRGs, sciatic nerve, and hind-paw intra-plantar skins were collected to assess neuroprotective effect of HGWD on PIPN. Next, network pharmacology was performed to decipher the potential active components and molecular mechanisms of HGWD, as were further verified by western blotting analyses in PIPN rats. Finally, the effect of HGWD on the chemotherapeutic activity of paclitaxel was evaluated in vitro and in vivo. Results In rats with PIPN, HGWD reversed mechanical allodynia, thermal hyperalgesia, and ameliorated neuronal damage. Moreover, HGWD significantly increased the level of nerve growth factor, dramatically reduced IL-1β, IL-6, TNF-α levels and oxidative stress. Network pharmacology analysis revealed 30 active ingredients in HGWD and 158 candidate targets. Integrated pathway analysis identified PI3K/Akt and toll-like receptor as two main pathways responsible for the neuroprotective effect of HGWD. Further experimental validation demonstrated that HGWD expectedly inhibited the protein expression of TLR4, MyD88, IKKα, and p-NF-κB, and promoted PI3K, p-Akt, Nrf2, and HO-1 level in dorsal root ganglia. Last but not least, HGWD did not interfere with the antitumor activity of paclitaxel both in in vitro and in vivo models. Conclusion These combined data showed that HGWD could inhibit paclitaxel-evoked inflammatory and oxidative responses in peripheral nervous system viaTLR4/NF-κB and PI3K/Akt-Nrf2 pathways involvement. The neuroprotective property of HGWD on PIPN provides fundamental support to the potential application of HGWD for counteracting the side effects of paclitaxel during chemotherapy.

Over 800 million people globally suffer from chronic kidney disease (CKD). Maternal obesity has emerged as a risk factor for CKD in offspring, but the mechanisms remain unclear. In this study, we use mouse models of maternal obesity to investigate macrophage involvement in offspring kidneys. Multi-omics analyses revealed that maternal obesity accelerates kidney disease in male offspring through dysregulated crosstalk between proximal tubules (PT) and macrophages. PT-derived 20-hydroxyeicosatetraenoic acid (20-HETE) promotes mitochondrial hyperactivity and macrophage to myofibroblast transition (MMT) via Ffar1 in macrophages. Targeting 20-HETE or depleting Ffar1 in offspring of obese mothers markedly reduces kidney pathology. Hormone screening identified 3,3,5-Triiodo-L-thyronine (T3) as a factor that enhances Ffar1 expression in macrophages. Mechanistically, the T3 receptor (TRβ) binds to an enhancer we identify upstream of the gene, promoting Ffar1 transcription via the TRβ-P300-BRD4 regulatory axis. These findings highlight T3 and 20-HETE co-activated MMT as a central mechanism to kidney disease in offspring of obese mothers, offering potential therapeutic targets. Maternal obesity is a risk factor for developing chronic kidney disease in the offspring later in life. Here the authors study male offspring in a mouse model of maternal obesity and identify dysregulated metabolism due to disrupted crosstalk between proximal tubules and macrophages as an important mechanism.

Clear cell renal cell carcinoma (ccRCC) is the most frequently occurring malignant tumor within the kidney cancer subtype. It has low sensitivity to traditional radiotherapy and chemotherapy, the optimal treatment for localized ccRCC has been surgical resection, but even with complete resection the tumor will be eventually developed into metastatic disease in up to 40% of localized ccRCC. For this reason, it is crucial to find early diagnostic and treatment markers for ccRCC. We obtained anoikis-related genes (ANRGs) integrated from Genecards and Harmonizome dataset. The anoikis-related risk model was constructed based on 12 anoikis-related lncRNAs (ARlncRNAs) and verified by principal component analysis (PCA), Receiver operating characteristic (ROC) curves, and T-distributed stochastic neighbor embedding (t-SNE), and the role of the risk score in ccRCC immune cell infiltration, immune checkpoint expression levels, and drug sensitivity was evaluated by various algorithms. Additionally, we divided patients based on ARlncRNAs into cold and hot tumor clusters using the ConsensusClusterPlus (CC) package. The AUC of risk score was the highest among various factors, including age, gender, and stage, indicating that the model we built to predict survival was more accurate than the other clinical features. There was greater sensitivity to targeted drugs like Axitinib, Pazopanib, and Sunitinib in the high-risk group, as well as immunotherapy drugs. This shows that the risk-scoring model can accurately identify candidates for ccRCC immunotherapy and targeted therapy. Furthermore, our results suggest that cluster 1 is equivalent to hot tumors with enhanced sensitivity to immunotherapy drugs. Collectively, we developed a risk score model based on 12 prognostic lncRNAs, expected to become a new tool for evaluating the prognosis of patients with ccRCC, providing different immunotherapy strategies by screening for hot and cold tumors.

The potential use of privately-owned autonomous vehicles (AVs) for the evacuation of carless households threatened by hurricanes is underexplored. Based on 518 original survey responses from South Carolina (SC) residents, an ordered logistic model was developed to determine the willingness of individuals to temporarily share their AVs for evacuation without their presence. The model results indicated that respondents who (a) were unemployed, (b) had experience giving disaster relief assistance, (c) took regular religious trips and were more comfortable with AVs (d) delivering packages and (e) being purchased and shared for income in the next five years were more willing to share for evacuation. Respondents who (a) were aged 65 or older, (b) had income below $15,000 per year, and (c) had less than two social media accounts were less willing to share. The model was applied to a state-wide synthetic population to simulate a disaster scenario in SC under different AV market penetration (p) scenarios to determine the potential use of AVs for evacuation assistance. Monte Carlo simulation results indicated that the percentage of households that can be evacuated increased linearly with respect to p, by 5.5% for every 1% increase in p until p was nearly 20%. When p was 30% or higher, the number of shared AVs was sufficient to evacuate all households in need. Therefore, in SC, if privately-owned AVs are widely available, they could serve as a viable alternative or be used to supplement the traditional evacuation programs that rely on buses.

Objective To evaluate the efficacy of Tuina (Chinese therapeutic massage) manipulation plus horse-riding squat exercise in treating knee osteoarthritis (KOA) and optimize the combining protocol. Methods Based on a 2×2 factorial design, 120 eligible KOA patients were randomized into a manipulation group (group A 1 B 2 ), a manipulation plus horse-riding squat group (group A 1 B 1 ), a sitting knee-adjustment group (group A 2 B 2 group), and a sitting knee-adjustment plus horse-riding squat group (group A 2 B 1 ), with 30 cases in each group. The intervention was conducted three times a week, lasting for four weeks. The Western Ontario and McMaster Universities osteoarthritis index (WOMAC) was taken as the major measure for efficacy evaluation (including three component scores, pain, stiffness, and daily function, and total score). Results The three component scores (pain, stiffness, and daily function) and the total score of WOMAC showed significant differences after the intervention in the four groups ( P <0.05). There were significant inter-group differences in the WOMAC stiffness score amongst the four groups after the intervention ( P <0.05). In group A 1 B 1 , the step length, stride, walking speed, and knee joint flexion angle changed significantly after treatment ( P <0.05). After the intervention, the step length changed significantly in group A 1 B 2 ( P <0.05), and the walking speed changed significantly in group A 2 B 1 ( P <0.05). There were no significant differences in the step length, stride, walking speed, or knee joint flexion angle among the four groups ( P >0.05). The extensor peak torque at 180 °/s changed significantly in group A 1 B 2 after treatment ( P <0.05). Neither the intra-group nor the inter-group comparisons of the four groups revealed significant differences in the other isokinetic muscle strength parameters ( P >0.05). The main effect of manipulation showed significant in affecting the WOMAC pain and total scores ( P <0.05). The main effect of horse-riding squat exercise showed significant in affecting the WOMAC pain and stiffness scores ( P <0.05). Conclusion The four treatment protocols all can improve the symptoms of KOA, for instance, relieving pain and stiffness, and enhancing daily function. Group A 2 B 1 produces the most eminent effect in relieving joint stiffness. The main effects of both manipulation and horse-riding squat exercise are significant in reducing pain. Besides, the main effect of horse-riding squat exercise is significant in relieving joint stiffness.

Nonalcoholic fatty liver disease is the most common chronic liver disease. Fatty pancreas has also been described but is difficult to assess. It is now possible to measure pancreatic and liver fat accurately with magnetic resonance imaging (MRI). We aimed to define the normal range of pancreatic fat and identify factors associated with fatty pancreas. In addition, the effect of fatty liver and fatty pancreas on insulin resistance (IR) and pancreatic β-cell function was studied. Fat-water MRI and proton-magnetic resonance spectroscopy were performed on 685 healthy volunteers from the general population to measure pancreatic and liver fat, respectively. On the basis of fasting plasma glucose and insulin levels, the IR and β-cell function were assessed using the homeostasis model assessment (HOMA). Among subjects without significant alcohol consumption or any component of metabolic syndrome, 90% had pancreatic fat between 1.8 and 10.4%. Using the upper limit of normal of 10.4%, 110 (16.1%; 95% confidence interval 13.3-18.8%) subjects had fatty pancreas. On multivariable analysis, high serum ferritin, central obesity, and hypertriglyceridemia were independent factors associated with fatty pancreas. Subjects with both fatty pancreas and fatty liver had higher HOMA-IR than did those with either condition alone. Fatty pancreas was not associated with HOMA-β after adjusting for liver fat and body mass index. In all, 16.1% of this community cohort of adult Hong Kong Chinese volunteers had a fatty pancreas by our definition. Central obesity, hypertriglyceridemia, and hyperferritinemia are associated with fatty pancreas. Individuals with fatty pancreas have increased IR.

Humanoid robot has been concerned as it can perform some movements as human, especially imitating human motion in real time with motion tracking equipments. To imitate the human motion, there are still some challenges for the lower-body control of robot due to the physical difference between human and robot. In this paper, we propose a joint angle-based control (JAC) scheme for the lower-body control of humanoid robot to imitate human motion via Kinect sensor. Due to factors such as noise, tracking error and robot joint constrains, the motion information captured from the Kinect sensor applied to the robot directly will arise the problem of balance control. To overcome it, we optimize the joint angles in the lower-body of NAO, and define a gain factor to compensate the difference between the human motion and the robot so as to keep the balance of humanoid robot during imitation. Experimental results show that the proposed control scheme works efficiently even when the humanoid robot performs some complex movements such as standing on single foot.

Palbociclib plus an aromatase inhibitor is approved for treatment of patients with ER+/HER2- advanced breast cancer (ABC). In the PALOMA-4 trial, adding palbociclib to letrozole prolonged median progression-free survival in Asian women with ER+/HER2- ABC. Here, we report patient-reported outcomes (PROs) from PALOMA-4. PALOMA-4 was a randomized, double-blind, phase 3 trial of palbociclib plus letrozole vs. placebo plus letrozole treatment in postmenopausal Asian women with ER+/HER2- ABC. PROs were longitudinally assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQoL 5D three level (EQ-5D-3L) questionnaires. Group comparisons were analyzed using longitudinal, mixed-effects models. Patients were randomly assigned to palbociclib plus letrozole (n = 169) or placebo plus letrozole (n = 171) treated groups. No significant between-arm differences in change from baseline were observed in FACT-B and its subscales, or the EQ-5D-3L index. A significant, but not clinically meaningful difference was observed in change from baseline in mean EQ-VAS score favoring palbociclib plus letrozole (3.36; 95% confidence interval [CI], 0.88-5.83; P = 0.008). When patients from both arms were combined, significant differences in the mean change from baseline for FACT-B total were observed favoring treatment responders vs. non-responders (3.84; 95% CI, 0.33-7.36; P = 0.032) and for the Breast Cancer Subscale favoring patients without disease progression vs. those with progression (0.97; 95% CI, 0.05-1.89; P = 0.038). Quality of life was maintained when palbociclib was added to letrozole in Asian women with ABC. These findings are consistent with PALOMA-2 results and support the use of palbociclib as first-line treatment in postmenopausal Asian patients with ER+/HER2- ABC. clinicaltrials.gov, NCT02297438.