Natural killer (NK) cells contribute to liver transplant (LTx) rejection. However, the blood-circulating NK-cell dynamics of patients who experience acute rejection (AR) are unclear. Herein, we longitudinally profiled the total NK cells and their subsets, along with the expression of activating and inhibitory receptors in sequential peripheral blood mononuclear cell samples, spanning from before LTx to the first year after LTx of 32 patients with AR and 30 patients under a steady immune status. Before transplantation, patients with AR (rejectors) contained a significantly higher proportion of the immature CD56^brightCD16^– subset and a lower cytolytic CD56^dimCD16⁺ in the total blood-circulating NK cells than patients with steady immunity. Both subsets contained a high NKp30-positive population, and CD56^dimCD16⁺ additionally exhibited a high NKp46-positive ratio. The NKp30-positive ratio in CD56^dimCD16⁺ subset showed the most prominent AR predictive ability before LTx and was an independent risk factor of LTx AR. After transplantation, the blood-circulating NK cells in rejectors maintained a higher CD56^brightCD16⁻ and lower CD56^dimCD16⁺ composition than the controls throughout the first year after LTx. Moreover, both subsets maintained a high NKp30-positive ratio, and CD56^dimCD16⁺ retained a high NKp46-positive ratio. The blood-circulating NK cell subset composition was consistent during AR, while the expressions of NKp30 and NKp46 were augmented. Collectively, a more immature CD56^brightCD16⁻ subset composition and an activated phenotype of high NKp30 expression were the general properties of blood-circulating NK cells in rejected LTx recipients, and the NKp30-positive ratio in CD56^dimCD16⁺ NK subset before LTx possessed AR predictive potential.

Hepatocyte proliferation restores liver mass after partial hepatectomy (PHx), but the metabolic cost of this process remains unclear. Single‐nucleus transcriptomics of mouse liver 48 h after 70% PHx revealed that EGFR–FOXM1 signalling drives mitotic entry while simultaneously suppressing PPARα–ACSL1‐mediated lipid catabolism. Consequently, triglycerides and free fatty acids accumulate in regenerating tissue. Activating PPARα with the agonist Wy‐14643 released this metabolic brake, accelerated hepatocyte proliferation via HIF1α‐FOXM1, and improved post‐PHx recovery. These data identify lipid‐metabolic reprogramming as an EGFR‐dependent collateral effect that can be pharmacologically reversed to enhance liver regeneration in surgical patients, offering a readily translatable strategy to reduce post‐operative liver failure and shorten hospital stay after major hepatectomy.

T cells are key mediators of alloresponse during liver transplantation (LTx). However, the dynamics of donor-reactive T-cell clones in peripheral blood during a clinical T-cell–mediated rejection (TCMR) episode remain unknown. Here, we collected serial peripheral blood mononuclear cell samples spanning from pre-LTx to 1 year after LTx and available biopsies during the TCMR episodes from 26 rejecting patients, and serial peripheral blood mononuclear cell samples were collected from 96 nonrejectors. Immunophenotypic and repertoire analyses were integrated on T cells from rejectors, and they were longitudinally compared to nonrejected patients. Donor-reactive T-cell clone was identified and tracked by cross-matching with the mappable donor-reactive T-cell receptor repertoire of each donor-recipient pair in 9 rejectors and 5 nonrejectors. Before transplantation, the naive T-cell percentage and T-cell receptor repertoire diversity of rejectors was comparable to that of healthy control, but it was reduced in nonrejectors. After transplantation, the naïve T-cell percentages decreased, and T-cell receptor repertoires were skewed in rejectors; the phenomenon was not observed in nonrejectors. Alloreactive clones increased in proportion in the peripheral blood of rejectors before TCMR for weeks. The increase was accompanied by the naïve T-cell decline and memory T-cell increase and acquired an activated phenotype. Intragraft alloreactive clone tracking in pre-LTx and post-LTx peripheral blood mononuclear cell samples revealed that the pretransplant naïve T cells were significant contributors to the donor-reactive clones, and they temporarily increased in proportion and subsequently reduced in blood at the beginning of TCMR. Together, our findings offer an insight into the dynamic and origin of alloreactive T cells in clinical LTx TCMR cases and may facilitate disease prediction and management.

Background: Early postoperative infection (EPI) is common in elderly patients with hepatocellular carcinoma (HCC) and is associated with poor prognosis. Effective risk prediction tools are urgently needed for early identification. This study aimed to develop and validate an inflammation-, nutrition-, and surgery-based INSEP nomogram model for predicting EPI-related adverse events in this population. Methods: A total of 988 elderly HCC patients from two medical centers were retrospectively enrolled and randomly divided into a training dataset ( n = 692) and an internal validation dataset ( n = 296), while 381 patients from a third medical center served as an external validation dataset. Restricted cubic spline (RCS), receiver operating characteristic (ROC), least absolute shrinkage and selection operator (LASSO), and multivariable logistic regression analyses were performed to identify independent predictors of EPI and develop the INSEP nomogram. An online risk calculator was established, and model performance was assessed using ROC, calibration, decision curve, and clinical impact curve analyses. Results: The INSEP model incorporated five independent predictors: SII ≥600 (OR 2.73, p = 0.023), CONUT ≥ 3 (OR 7.84, p < 0.001), ECOG 2–4 (OR 4.96, p < 0.001), laparoscopic surgery (OR 0.83, p = 0.025), and surgical duration ≥180 min (OR 7.44, p < 0.001). The model achieved AUCs of 0.870 in the training dataset, 0.803 in internal validation, and 0.798 in external validation, with good calibration and clinical utility. Two representative case demonstrations confirmed the model's accurate risk stratification: a low-risk patient (predicted EPI 3.3%) had no infection, while a high-risk patient (predicted 97.0%) developed pneumonia. Usability testing by three independent hepatobiliary surgeons (6–10 years of experience) showed efficient operation (25–60 s per case), intuitive interface, and clear output, with no system errors identified. Conclusion: The INSEP model is a reliable and practical tool for individualized EPI risk assessment in elderly HCC patients undergoing curative hepatectomy, demonstrating good predictive performance, clinical applicability, and user acceptability.

Background: Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune cholestatic liver disease. Current first-line therapy, ursodeoxycholic acid (UDCA), yields suboptimal response rates, leaving many patients at risk of disease progression. Thus, novel therapeutic targets are urgently needed to slow PBC progression. Methods: We performed two-sample Mendelian randomization (MR) to identify proteins causally associated with PBC risk, using protein quantitative trait loci (pQTL) as genetic instruments. The discovery stage utilized PBC genome-wide association study (GWAS) summary statistics from Cordell et al., followed by replication in independent GWAS datasets from the IEU Open GWAS project and the FinnGen consortium. pQTL data were drawn from large-scale plasma (N = 2,656) and cerebrospinal fluid (CSF; N = 184) proteomic studies. We also conducted sensitivity analyses, including Bayesian colocalization, reverse-causality testing, and phenotype scanning. Identified protein targets were further examined via protein–protein interaction (PPI) network analysis. Results: Three proteins showed significant associations with PBC risk after Bonferroni correction ( p < 6.35 × 10 ⁻⁵ ). Elevated plasma MANBA (odds ratio [OR] = 1.29, 95% confidence interval [CI] 1.20–1.40, p = 1.22 × 10 ⁻¹⁰ ) and CSF TNFSF15 (OR = 6.37, 95% CI 2.94–13.83, p = 2.79 × 10 ⁻⁶ ) were associated with higher PBC risk, whereas elevated plasma FCRL3 (OR = 0.79, 95% CI 0.73–0.86, p = 2.12 × 10 ⁻⁸ ) was associated with lower risk. Bayesian colocalization analysis indicated that these protein loci and PBC share the same underlying causal variants. Conclusion: Elevated plasma MANBA and CSF TNFSF15 levels were linked to increased PBC risk, while higher plasma FCRL3 was protective. Our findings nominate MANBA and TNFSF15 as potential therapeutic targets, while FCRL3 may serve as a protective biomarker for PBC management.