https://www.nature.com/articles/s41392-026-02773-7
chatGPT(6AstraMaxPaid):
Yang et al. (2026), “Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK”, presents promising mouse evidence that hepassocin supports liver maintenance and recovery after surgery. The functional findings are interesting, but the claims about reversing ageing and establishing AMPK dependence exceed what is demonstrated. There is also a specific statistical reporting inconsistency.
This assessment covers the uploaded main article and figures. The separate supplementary files were not available for direct inspection.
The study investigates hepassocin, also called HPS or fibrinogen-like protein 1, a protein secreted mainly by the liver. The authors compare normal mice with mice lacking HPS, principally at 3 and 12 months of age, and examine regeneration after surgical removal of approximately 70% of the liver.
| Main finding | Evidence reported |
|---|---|
| HPS decreases with age | Lower circulating and liver HPS in older mice; lower circulating HPS across age groups in 94 human participants. |
| HPS deficiency worsens liver abnormalities | Twelve-month-old knockout mice had more liver fat, insulin resistance, senescence-associated markers and impaired autophagy. |
| HPS becomes more important for regeneration with age | Seven-day survival after surgery was approximately 87% in 12-month-old normal mice and 40% in knockout mice, with 15 animals per group. All young mice survived. |
| AMPK stimulation improves the knockout phenotype | Seven days of AICAR treatment reduced senescence-associated markers and improved liver regeneration and postoperative survival. |
| HPS replacement has beneficial effects | Recombinant HPS improved regeneration in normal 12-month-old mice and improved survival and senescence-associated markers in knockout mice. |
The proposed mechanism begins with HPS interacting with Annexin A2, or ANXA2, at the hepatocyte surface. This activates a signalling sequence involving ERK, p90RSK, LKB1 and then AMPK. Downstream changes favour autophagy, restrain mTOR signalling and alter lipid metabolism.
The authors suggest that younger mice compensate for HPS loss through other pathways, including STAT3 and CaMKK signalling. That explanation is plausible, but the proposed compensation is not directly established by blocking those pathways.
The main novelty is the age-dependent requirement for HPS and the proposed connection between its receptor machinery and AMPK. Specifically:
- An age-dependent phenotype: HPS loss has relatively modest effects in young animals but substantially compromises liver maintenance and regeneration by 12 months.
- A proposed ANXA2 signalling mechanism: Binding experiments, protein interaction studies and knockdown experiments connect HPS to the ANXA2-ERK-p90RSK-LKB1-AMPK pathway.
- Treatment effects in normal mice: Improving regeneration in animals that retain their HPS gene makes the findings more relevant than replacement experiments in knockout animals alone.
HPS itself, its liver-protective actions and its effects on hepatocyte proliferation were already known. Earlier work from this group also showed protection against experimental steatohepatitis. The advance is therefore an extension into age-associated dysfunction with additional mechanistic detail. Earlier HPS study, 2022
The strongest feature of the experimental design is its combination of genetic deletion, replacement treatment and functional outcomes. The authors measure postoperative survival, liver mass recovery and hepatocyte proliferation alongside molecular markers. Their use of chloroquine and a dual-fluorescence LC3 reporter also strengthens the evidence for impaired autophagic processing.
My principal criticisms are:
-
The statistical reporting contains an important inconsistency.
Figure 3 states that there are three samples per group and that comparisons use the Mann-Whitney test, yet displays significance levels extending to p < 0.0001.
With three independent observations in each group, the smallest possible conventional exact two-sided Mann-Whitney p-value is 0.10. The stated sample sizes, test and significance annotations therefore do not reconcile.
This could reflect an incorrect test label or sample-size description, rather than invalid underlying observations. Nevertheless, it requires clarification and reanalysis before accepting the reported significance levels.
-
AMPK involvement is supported, but its necessity for HPS protection is not demonstrated.
HPS increases AMPK phosphorylation, and AICAR improves outcomes when HPS is absent. These findings support AMPK participation.
However, activating a pathway can compensate for a defect without proving that the original protective factor must act through that pathway. A stronger experiment would test whether HPS still improves regeneration when AMPK is specifically deleted from hepatocytes. The LKB1 knockdown experiments strengthen the signalling model but do not answer that central question.
-
Reduced senescence markers do not establish reversal of senescence in individual cells.
The authors measure p16, p21, senescence-associated beta-galactosidase, lipofuscin and SASP-related transcripts. Together, these support a senescence-associated phenotype.
Their reduction after treatment could reflect reduced stress, altered inflammatory signalling, clearance of damaged cells or expansion of healthier cells. The experiments do not track previously senescent hepatocytes and show that those same cells recover durable normal function. Furthermore, SASP-related RNA measurements do not directly establish secretion of the corresponding proteins.
-
The ageing model has limited scope.
Twelve-month-old mice are middle-aged, as the authors acknowledge. Results at this age do not establish efficacy in substantially older animals.
The knockout is also lifelong and affects the whole body. Consequently, systemic metabolic effects and developmental adaptation may contribute to the liver phenotype. An inducible, hepatocyte-specific knockout would better isolate the immediate role of hepatic HPS.
No lifespan or sustained healthspan benefit is demonstrated.
-
Some discussion claims extend beyond the treatment experiments shown.
Figure 6 demonstrates improved regeneration in normal mice. However, its lipofuscin, p16, p21 and SASP-marker rescue experiments are performed in knockout mice.
The discussion nevertheless describes restoration of senescence markers in aged normal animals. That broader claim is not established by the displayed experiments.
Treatment was also given for seven days before surgery. The evidence therefore supports preoperative conditioning; efficacy when treatment begins after injury remains untested.
-
The human evidence is associative and potentially confounded.
The circulating HPS results are cross-sectional. They cannot establish whether falling HPS causes deterioration or reflects other changes accompanying age.
The human liver protein measurements come from non-tumour tissue adjacent to hepatocellular carcinomas in 152 patients. Such tissue is not equivalent to healthy ageing liver, and underlying disease could influence the association.
-
Long-term safety needs particular attention because HPS also regulates immunity.
FGL1 has been identified as a ligand for the inhibitory immune receptor LAG-3, with effects on antitumour T-cell responses. That creates a substantive question about sustained HPS supplementation, especially around cancer surgery. Wang et al., Cell, 2019
This does not establish that HPS treatment increases cancer risk. It means that short-term tolerability and improved regeneration cannot settle the longer-term balance between tissue repair and tumour surveillance.
For the citrate and acetyl-CoA axis, the relevant connection is AMPK regulation of acetyl-CoA carboxylase, or ACC. Inhibiting ACC can reduce the use of acetyl-CoA for fatty acid synthesis. However, this paper does not measure citrate export, compartment-specific acetyl-CoA, histone acetylation or splicing. Any proposal that HPS preserves acetyl-CoA for nuclear functions remains a hypothesis requiring direct metabolic and chromatin measurements.