Researchers used least absolute shrinkage and selection operator regression followed by multivariable logistic regression to identify independent predictors of fibrosis. They then developed HEP-FIB from routinely available laboratory parameters, including platelet count, liver-function measures and lipid biomarkers. The score’s diagnostic performance was assessed with ROC-curve analysis, bootstrap internal validation and calibration analysis, and was compared with established non-invasive indices: APRI, FIB-4 and GPR. Ten machine-learning algorithms were also constructed and evaluated using measures of discrimination, classification performance, calibration and overall predictive ability. Decision curve analysis was used separately for HEP-FIB and the machine-learning models to examine clinical utility.

At an optimal HEP-FIB cutoff of 4 or higher, the score had a sensitivity of 78%, specificity of 89% and overall accuracy of 88%. Its AUC was higher than those for APRI, FIB-4 and GPR, which were 0.724, 0.654 and 0.773, respectively; all three comparisons had p values below 0.001 by the DeLong test. Bootstrap validation produced an optimism-corrected AUC of 0.881. Calibration analysis indicated good agreement between predicted and observed fibrosis probabilities, while decision curve analysis favored HEP-FIB over the default strategies assessed.

XGBoost performed best among the machine-learning approaches in the validation dataset, with an AUC of 0.914, accuracy of 0.88, sensitivity of 0.72, specificity of 0.93, balanced accuracy of 0.83 and Matthews correlation coefficient of 0.74. Its Brier score was 0.095, and the reported false-positive and false-negative rates were 0.062 and 0.275, respectively. The machine-learning models showed a marginal performance advantage over HEP-FIB and greater net clinical benefit than test-all and test-none strategies in decision curve analysis. These findings come from a retrospective cohort at one center and were supported only by internal bootstrap validation. The study did not establish performance in independent or diverse populations, so the results do not yet establish routine clinical use or replacement of existing fibrosis-assessment methods.

Subject of Research: Internal validation of HEP-FIB and machine-learning models for non-invasive prediction of significant hepatic fibrosis in chronic hepatitis B

Article Title: Novel HEP-FIB score combined with machine learning models for non-invasive prediction of significant hepatic fibrosis in chronic hepatitis B patients: a single-center, internally validated study

Article References: Bashir, A., Arora, R., Mehrotra, D., Bala, M., Parry, A. H., & Iqball, A. (2026). Novel HEP-FIB score combined with machine learning models for non-invasive prediction of significant hepatic fibrosis in chronic hepatitis B patients: a single-center, internally validated study. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14508-8

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14508-8

Keywords: chronic hepatitis B, hepatic fibrosis, HEP-FIB, machine learning, XGBoost, non-invasive testing, diagnostic accuracy, internal validation, clinical utility, Novel, score, combined

Hepatic fibrosis is the accumulation of excess extracellular matrix, chiefly collagen, that follows chronic liver injury from causes such as viral hepatitis, alcohol use, fatty liver disease, and cholestatic disorders. Left unchecked, it progresses to cirrhosis and dramatically raises the risk of hepatocellular carcinoma. At the center of the scarring process are hepatic stellate cells, quiescent vitamin A-storing cells that, when activated by inflammatory cues, transform into myofibroblast-like cells that pump out matrix proteins. The immune microenvironment surrounding these cells, particularly the behavior of macrophages, largely determines whether injury resolves or spirals into permanent scarring. Macrophages are famously plastic: they can polarize toward a classically activated M1 state, marked by production of tumor necrosis factor-alpha and interleukin-1 beta, or toward an alternatively activated M2 state, associated with transforming growth factor beta and tissue remodeling. Both extremes, paradoxically, can feed fibrosis, one by fueling inflammation and the other by driving matrix deposition.

What the new study adds is a nervous system connection to this immunological drama. The researchers began by examining liver tissue from cirrhotic and non-cirrhotic human subjects, with informed consent and ethical approval from Tangdu Hospital, and then modeled fibrosis in mice using two complementary approaches: repeated intraperitoneal injection of carbon tetrachloride, a hepatotoxin that causes oxidative injury, and a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet, which induces cholestatic damage. Across both human samples and both mouse models, NPY levels rose in fibrotic livers. Crucially, the source of that NPY was not the liver cells themselves but intrahepatic sympathetic nerves, identified through markers such as tyrosine hydroxylase. The finding places the sympathetic nervous system, the branch that mediates fight-or-flight responses, in direct molecular contact with the liver’s immune landscape.

The team next asked which cells were listening. NPY signals through a family of G protein-coupled receptors, and the investigators mapped their distribution carefully. Two of them, NPY1R and NPY2R, were significantly increased in fibrotic liver and localized specifically to hepatic macrophages, while the related NPY4R and NPY5R did not show the same pattern. This receptor specificity matters, because it narrows a broad neuropeptide signal down to a defined cellular target and suggests that the macrophage is the critical relay station between sympathetic nerve activity and fibrogenesis.

To test causality rather than mere correlation, the researchers turned to genetics and gene silencing. In NPY-knockout mice subjected to the fibrosis protocols, liver injury, collagen deposition, and inflammation were all significantly reduced. Flow cytometry and molecular profiling of the animals’ macrophages revealed that the deletion suppressed both M1 and M2 polarization, indicating that NPY was not simply tipping the balance between the two states but amplifying the entire profibrotic immune program. When the team silenced NPY1R or NPY2R in the liver in vivo using adeno-associated virus vectors, the protective phenotype was recapitulated, confirming that the receptors were the necessary conduits for NPY’s fibrogenic effects.

The mechanistic heart of the paper lies in the downstream signaling dissection, performed in vitro with bone marrow-derived macrophages. The researchers found that NPY engages a PI3K-dependent cascade in both polarization directions, but the pathways diverge at a key kinase node. For M1 polarization, NPY acting through NPY1R and NPY2R activates the PI3K-PAK1-c-Jun axis, with c-Jun, a component of the AP-1 transcription factor complex, driving the inflammatory gene program. For M2 polarization, the signal instead flows through PI3K-PAK1 to RSK, a ribosomal S6 kinase, promoting the alternative activation program. Blocking the corresponding receptors or the downstream kinases pharmacologically in vitro abolished these effects, allowing the authors to draw a solid, experimentally validated map from neuropeptide to receptor to kinase to transcription factor to macrophage phenotype.

The final link in the chain connects macrophages back to stellate cells. Polarized macrophages release a cocktail of profibrotic cytokines, including TNF-alpha, IL-1 beta, TGF-beta, and platelet-derived growth factor BB, which are well-established activators of hepatic stellate cells. By supercharging both macrophage states, NPY effectively raises the volume of the profibrotic conversation between immune cells and matrix-producing cells. The authors are careful to distinguish what has been proven from what remains plausible: the receptor-PI3K-PAK1 cascades are experimentally validated, whereas a direct NPY effect on stellate cells and the precise macrophage-stellate cell crosstalk remain putative, unvalidated interactions in their model. That transparency is a useful reminder of where the science currently stands.

The therapeutic implications are considerable. Current antifibrotic options are limited, and most strategies target downstream consequences of injury rather than upstream regulatory circuits. If sympathetic nerve-derived NPY is a genuine driver of fibrogenesis, then NPY1R and NPY2R become attractive drug targets, and receptor antagonists, some of which have already been developed for metabolic and cardiovascular research, could in principle be repurposed or refined. The dual role of NPY in pushing macrophages toward both inflammatory and profibrotic states suggests that receptor blockade might dampen fibrosis through two mechanisms simultaneously. At the same time, the systemic importance of NPY in appetite regulation, vascular tone, and stress physiology means that any clinical strategy would need to navigate a narrow therapeutic window, likely favoring targeted delivery to the liver or selective peripheral receptor antagonism over systemic neuropeptide depletion.

The study also contributes to a rapidly growing appreciation of neuroimmune crosstalk in chronic disease. The idea that nerves do more than transmit sensation and regulate tone, that they actively sculpt local immune responses through neuropeptide release, has gained traction in fields ranging from intestinal inflammation to tumor immunology. This work extends that framework to the liver, an organ densely innervated at portal triads and richly supplied by sympathetic fibers, and identifies a concrete molecular itinerary by which neural input becomes fibrotic output. It raises provocative questions about whether chronic stress, which elevates sympathetic outflow and systemic NPY, might modulate fibrosis progression in patients, a hypothesis the current study does not directly test but which its findings make testable.

Caveats remain, as they do in any preclinical study. The mouse models, carbon tetrachloride injury and DDC diet, are established but imperfect proxies for the heterogeneous fibrotic diseases seen in clinics, and the human tissue analysis, while consistent with the animal data, is observational. Whether NPY receptor blockade can safely slow or reverse established fibrosis in patients will require medicinal chemistry, pharmacokinetics, and eventually clinical trials that this paper does not provide. Still, by connecting sympathetic nerves, macrophage polarization, PI3K-MAPK signaling, and stellate cell activation into a single coherent pathway, the Xi’an team has converted a diffuse suspicion that the nervous system matters in liver disease into a specific, targetable hypothesis. For the millions of people living with chronic liver disease worldwide, that specificity is precisely what the field needs.

Subject of Research: Neuroimmune signaling by neuropeptide Y in macrophage polarization and hepatic fibrosis

Article Title: NPY promotes macrophage polarization and hepatic fibrogenesis via PI3K/MAPK-dependent neuroimmune mechanisms

Article References: Lin, Q., Zheng, X., Dou, W., Bai, Q., Liang, S., Kou, Z., Guo, H., Ding, Y., Zhao, S., Wang, J., Yin, J., & Liu, Z. (2026). NPY promotes macrophage polarization and hepatic fibrogenesis via PI3K/MAPK-dependent neuroimmune mechanisms. Cellular and Molecular Life Sciences, 83(1), Article 346. https://doi.org/10.1007/s00018-026-06428-2

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06428-2

Keywords: neuropeptide Y, hepatic fibrosis, macrophage polarization, NPY1R, NPY2R, PI3K signaling, MAPK, sympathetic nervous system, hepatic stellate cells, liver cirrhosis, neuroimmune crosstalk, cytokines

The team began by dissecting the chemistry of the roasted tea. Using colorimetric assays and high-performance liquid chromatography, they quantified the major constituents of the extract. Tea polyphenols dominated at roughly 287 milligrams per gram, followed by catechins at about 138 milligrams per gram, with tea polysaccharides, caffeine, and free amino acids rounding out the profile. Among individual catechins measured against authentic standards, EGCG led at 7.959 milligrams per gram, with catechin, catechin gallate, epigallocatechin, and gallic acid also present in appreciable amounts. Roasting, the authors note, does not merely add flavor; it restructures the active compound inventory, creating the material basis for the tea’s antioxidant, anti-inflammatory, and metabolic effects.

To test whether these compounds could counter aging, the researchers turned to a widely used model in which mice receive daily injections of D-galactose, a sugar that accumulates in tissues and drives oxidative stress, inflammation, and senescence-like damage. Male C57BL/6 mice were divided into four groups of ten: a control group receiving saline, a model group receiving D-galactose alone, and two treatment groups receiving D-galactose plus Nongxiang-type Tieguanyin extract by gavage at either 110 or 550 milligrams per kilogram per day for eight weeks. The doses were not arbitrary. The low dose was scaled from the typical daily tea consumption of Chinese adults, roughly five grams of dry leaves, using standard allometric conversion, while the high dose was set fivefold higher to probe dose dependence.

The behavioral results were striking. D-galactose-treated mice showed sharply reduced endurance on a treadmill, covering less distance before reaching exhaustion, and they faltered earlier on a rotating-rod fatigue test. High-dose tea extract reversed both deficits in a concentration-dependent manner. Grip strength, however, was unaffected, suggesting the compound acts on fatigue and metabolic capacity rather than raw muscle power. Metabolic cage measurements added a circadian dimension: D-galactose suppressed the mice’s 24-hour energy expenditure, with the loss concentrated in the dark phase when rodents are normally most active. High-dose Tieguanyin restored dark-phase energy expenditure to near-normal levels, hinting that the tea helps normalize the daily rhythm of metabolism that frays with age.

The liver emerged as the clear beneficiary. The elevated liver-to-body weight ratio caused by D-galactose fell back toward control values after tea treatment, while the heart, lungs, and kidneys showed no significant changes, indicating a liver-targeted effect. Serum levels of alanine aminotransferase and aspartate aminotransferase, the classic enzymes that spill into blood when hepatocytes are damaged, dropped in treated animals. Inside the liver, the chemical picture shifted just as decisively: levels of the antioxidant enzymes superoxide dismutase and glutathione, depleted by D-galactose, rebounded, while malondialdehyde, a marker of lipid peroxidation, declined. The authors suggest the liver’s own transport machinery may explain this selectivity, since hepatocytes actively take up tea polyphenols through organic anion-transporting polypeptides, concentrating the protective compounds where they are needed most.

Under the microscope, the damage and the rescue were both visible. Hematoxylin-eosin staining revealed that D-galactose had disrupted the architecture of hepatic lobules, disorganized hepatocytes, and loosened cytoplasm, abnormalities that tea treatment largely corrected. Masson staining, which dyes collagen blue, showed extensive fibrous proliferation in the aged livers that receded with treatment, and the fibrosis marker alpha-SMA fell in parallel at the protein level. Senescence itself left a measurable fingerprint: beta-galactosidase staining, a hallmark of senescent cells, lit up the D-galactose livers but faded with tea intervention. Western blotting completed the picture, showing that the senescence drivers P16, P21, and P53, which D-galactose had upregulated, were dialed back, while Sirt1, a longevity-associated deacetylase that D-galactose had suppressed, was restored.

To confirm the effect was not a rodent quirk, the team ran parallel experiments in cultured cells. They induced senescence in AML12 mouse hepatocytes and HepG2 human liver cancer cells using Nutlin-3a, a drug that activates p53-dependent senescence pathways. Co-treatment with the tea extract at one milligram per milliliter significantly reduced p16 and p21 protein levels in both cell lines and cut the fraction of blue-stained, senescence-positive cells. The consistency across mouse and human liver-derived cells strengthens the case that the anti-senescence activity is a genuine biological property of the extract rather than an artifact of one species or one model.

The mechanistic core of the study came from transcriptomics. Sequencing liver RNA revealed 1604 differentially expressed genes between D-galactose and control mice, and 3046 between D-galactose and high-dose tea mice, with 216 genes overlapping. Enrichment analyses converged on a single pathway: NF-κB, the master regulator of inflammatory transcription, was significantly activated by D-galactose and reversed by tea treatment. Gene set enrichment analysis confirmed the pattern, and western blots supplied the protein-level proof. D-galactose specifically increased the phosphorylation of the IKKα/β complex and of the p65 subunit, the molecular switch that releases NF-κB to enter the nucleus and ignite inflammatory gene expression. Tea extract suppressed both phosphorylation events in a dose-dependent fashion, while total protein levels stayed constant.

The authors frame this suppression as a direct counter to inflammaging, the chronic, low-grade inflammation that accompanies aging. Reactive oxygen species generated by dysfunctional mitochondria can activate the IKK complex through upstream kinases such as TAK1, and the tea’s restoration of antioxidant defenses likely starves that cascade of its trigger. The concurrent rise in Sirt1 adds a second brake, since Sirt1 can deacetylate p65 and dampen its transcriptional activity. The researchers are candid about limits: the D-galactose model captures oxidative stress-driven aging rather than the full complexity of natural senescence, and the cell experiments validated the phenotype rather than the upstream NF-κB axis, leaving causal validation for future work with naturally aged animals.

Even so, the translational arithmetic is tantalizing. The low mouse dose corresponds to about five grams of dry roasted Tieguanyin per day for a sixty-kilogram person, squarely within ordinary tea-drinking habits, while the high dose, equivalent to roughly twenty-five grams, could be reached through concentrated extracts or supplements. The authors envision the tea evolving from a traditional beverage into a functional food or anti-aging agent, pending clinical trials to confirm efficacy and optimal dosing in humans. For now, the study delivers something rarer than a health claim: a defined molecular pathway, verified at the levels of behavior, biochemistry, histology, transcriptome, and protein, through which a roasted oolong appears to slow the aging liver’s decline.

Subject of Research: Hepatoprotective and anti-senescence effects of roasted oolong tea extract in a D-galactose mouse aging model mediated by NF-κB pathway inhibition

Article Title: Protective Effects of Nongxiang‐Type Tieguanyin on the Liver of D‐Galactose‐Induced Aging C57BL/6 Mice via the NF‐κB Signaling Pathway

Article References: Chen, W., Li, M., Ye, L., Huang, D., Xiao, J., Sang, Y., Wang, Z., Yang, J., He, C., Chen, J., Zuo, Z., & Chen, X. (2026). Protective Effects of Nongxiang‐Type Tieguanyin on the Liver of D‐Galactose‐Induced Aging C57BL /6 Mice via the NF ‐ κB Signaling Pathway. Food Science & Nutrition, 14(10), Article e72396. https://doi.org/10.1002/fsn3.72396

Image Credits: AI Generated

DOI: 10.1002/fsn3.72396

Keywords: Tieguanyin, oolong tea, NF-κB signaling, liver aging, D-galactose, oxidative stress, cellular senescence, Sirt1, hepatic fibrosis, tea polyphenols, inflammaging, C57BL/6 mice