Introduction

Psoriasis, a chronic inflammatory dermatosis, clinically presents with erythematous papules and plaques predominantly affecting extensor surfaces (e.g., knees, elbows, scalp)1,2. These lesions profoundly impair patients’ quality of life and are frequently associated with psychological comorbidities including depression2. The recalcitrant nature of psoriasis, characterized by frequent relapses, poses significant therapeutic challenges in clinical practice, underscoring its detrimental impact on both physical and mental wellbeing3,4. Despite existing therapeutic options for psoriasis, significant clinical challenges persist, highlighting the need for innovative strategies41. Mesenchymal stem cells (MSCs) have emerged as a promising approach due to their immunomodulatory, tissue-repair capacities, ability to secrete bioactive molecules (e.g., cytokines, chemokines, growth factors) that regulate local immune microenvironments42,43, and multidirectional differentiation potential (into mesenchymal lineages like osteoblasts and non-mesenchymal types like hepatocytes)44. Notably, bidirectional crosstalk between MSCs and keratinocytes (KCs) is a core regulatory link in psoriasis pathogenesis: MSCs secrete pro-inflammatory cytokines inducing KC proliferation, and psoriasis-derived MSCs impair cell junctions to disrupt KC differentiation and shorten epidermal renewal45; conversely, psoriasis-derived KCs upregulate c-Myc, GLUT1, SCF, and EGF in control MSCs to enhance their metabolic activity and proliferation46. This crosstalk drives psoriasis’ hallmark cutaneous pathology (excessive proliferation, abnormal differentiation) via aberrant KC behavior, making MSCs a key research focus for treating psoriasis and similar inflammatory conditions.

Emerging evidence implicates dysregulated lipid metabolism as a key etiological factor. Psoriasis patients exhibit systemic dyslipidemia and elevated cardiovascular risks, notably atherosclerosis5, with frequent comorbidity of metabolic syndrome components including aberrant lipid profiles6. Beyond circulatory disturbances, lipid metabolite alterations are detectable within psoriatic skin tissue itself7,8. Correlative analyses indicate positive associations between epidermal lipid accumulation and disease severity9,10, while transcriptomic studies further confirm significant dysregulation of lipid-related pathways in lesional skin11, collectively highlighting the pathogenic centrality of metabolic dysfunction.

Adiponectin (ADIPOQ), among the earliest identified adipokines12, demonstrates inverse correlation with adipose mass—distinct from leptin and other adipocytokines13. This multifunctional hormone modulates glucose homeostasis, lipid metabolism, inflammatory responses, and fibrotic processes14. Murine models of adiponectin deficiency develop glucose intolerance and hyperlipidemia15,16, whereas transgenic overexpression improves metabolic parameters and attenuates obesity-related phenotypes17,18. Therapeutically, ADIPOQ exhibits insulin-sensitizing, anti-inflammatory, anti-atherogenic, and anti-neoplastic activities19, mediated partly through cell cycle arrest (via CCND1 suppression) and pro-apoptotic mechanisms (e.g., BAD upregulation) in malignant cells20.

Building upon our prior finding of significantly reduced ADIPOQ transcription in psoriatic lesions21, we hypothesized its involvement in disease-associated hyperproliferation. To test this, we supplemented psoriatic mesenchymal stem cells (MSCs) with exogenous ADIPOQ to evaluate its impact on lipid metabolic dynamics, subsequently employing MSC-NHEK coculture systems to assess keratinocyte proliferative responses.

Methods

Samples

Nine skin samples were collected from 9 psoriatic patients before treatment. Skin lesion samples from the control group were obtained from nine volunteers. All participants provided written informed consent prior to participation. The study was approved by the Medical Ethics Committee of Taiyuan Central Hospital (KY2022017) and carried out in accordance with the Declaration of Helsinki. All studies were conducted in accordance with national ethical guidelines for medical research.

Measurement of oxygen consumption rate (OCR)

The XF Substrate Oxidative Stress Test Kit (Agilent) enables sensitive assessment of mitochondrial function through targeted inhibition of three primary substrate pathways: Long-chain fatty acids (LCFAs): Inhibited by 4 µM Etomoxir (CPT1a inhibitor), Glucose/pyruvate (G/P): Inhibited by 2 µM UK5099 (mitochondrial pyruvate carrier/MPC inhibitor), Glutamine (Q): Inhibited by 3 µM BPTES (glutaminase 1/GLS-1 inhibitor). Cells (5 × 10⁵/well) were seeded in XF24-compatible plates. After 24-hour incubation in unbuffered medium (CO₂-free conditions), oxygen consumption rate (OCR) was measured with sequential injection of: Substrate inhibitors: Etomoxir (4 µM), UK5099 (2 µM), or BPTES (3 µM). Mitochondrial stress agents: Oligomycin (1.5 µM), FCCP (2.0 µM). Rotenone/Antimycin A (0.5 µM). Measurements included: basal respiration, acute inhibitor response (to Etomoxir/UK5099/BPTES), maximum respiratory capacity.

Bioinformatic analysis

The GSE166388 dataset was downloaded from the GEO (Gene Expression Omnibus) database (http://www.ncbi.nlm.nih.gov/geo/) and RStudio software (RStudio Integrated Development Environment, Version number: 4.3.1, https://www.r-project. org/) was used for analysis. DEG (Differentially expressed genes) analysis was performed using the limma package (linear models for microarray data, v3.54.0, https://bioinf.wehi.edu.au/limma/) in RStudio. The specific selection criteria were: Fold-change threshold: |log₂(fold change)| ≥ 1 (corresponding to ≥ 2-fold upregulation or ≤ 0.5-fold downregulation between psoriatic and healthy epidermis); Statistical significance threshold: Unadjusted p-value < 0.05; Quality control: Only genes with valid, non-duplicate gene symbol annotations (via the hgu133plus2.db database) were retained. Differentially expressed genes (DEGs) were expressed in the form of volcano map and heat map. In addition, the use of online tools from consonant suspathdb database (http://cpdb.olgen.mpg.de/) to KEGG (Kyoto Encyclopedia of Genes and Genomes, 1.42.0, https://www.bioconductor.org/packages/release/bioc/html/KEGGREST.html) enrichment analysis of DEGs, with P < 0.05 for selection criteria.

Treatment of cells

We transfected ADIPOQ and control plasmid into psoriatic and normal DMSCs to establish overexpression chains, and labeled them as “N-DMSC-Con”, “N-DMSC-ADIPOQ”, “P-DMSC-Con”, “P-DMSC-ADIPOQ”, respectively. The transfection of ADIPOQ was achieved by culturing MSCs in a 6-well plate until they grew to 80–90% confluence. Two micrograms of ADIPOQ or control vector, along with 6 µl of Lipofectamine 3000 reagent, were transfected into DMSCs. After 12 h, the medium was replaced with medium containing 5% FBS.

Co-culture of DMCSs with normal human epidermal keratinocytes

All 1 × 105 NHEK cells were cultured in epidermal growth factor-containing serum-free medium. They were inoculated at 1 × 104 cells/mL administered in 25 cm2 tissue culture flasks and maintained at 37 °C and 5% CO2. The medium was changed daily until the cells were confluent. NHEK was isolated using 0.25% trypsin and 0.04% EDTA. 3 × 105 NHEKs (2 × 105 cells/mL) were inoculated into the lower chamber of transwell plate, and DMSC transfected with Adipoq and con plasmid was inoculated into the upper chamber (concentration of 2 × 105 cells/mL) for co-culture. After co-culture for 72 h, NHEK was isolated by 0.25% trypsin-0.04% EDTA method. Subsequently, NHEKs were collected for further analysis.

Construction of psoriasis mouse model

Twelve C57BL/6 mice (6–8 weeks old, male) were selected, with 6 mice in each group (total 2 groups: IMQ + DMSO, IMQ + ADIPOQ). 5% imiquimod (IMQ) was applied topically to the back (approximately 2 cm2) of mice daily. After 5-day treatments, the treated skin was collected for HE and PCR. The IMQ + ADIPOQ treatment group was intraperitoneally injected with 0.8 mL of ADIPOQ (15ug/kg) after daily IMQ treatment. The “Skin Lesion Severity Score” was adapted from the Clinical Psoriasis Area and Severity Index (PASI) and modified for mouse models. It contains three core parameters, each of which scores within the range of 0 to 4 (0 = absent; 4 = most serious) : Erythema: Evaluated by visual inspection of the intensity and distribution of redness and swelling (0 = no redness and swelling; 1 = mild, local; 2 = moderate, patchy; 3 = severe, extensive; 4 = very severe, diffuse). Scales: Desquamation is evaluated through vision and touch (0 = no scales; 1 = fine, sparse; 2 = moderate, patchy; 3 = thick, extensive; 4 = very thick, extensive). Epidermal thickness: Quantified by H&E staining using ImageJ software. The scores were compared with those of the control mice (0 = thickness equivalent to that of the control mice; 1 = 1.1-2 times the control; 2 = 2.1-3 times the control; 3 = 3.1-4 times the control; 4 = ≥ 4 times the control). The final severity score for each mouse was the sum of the scores of three parameters (erythema + scaling + epidermal thickness).

Before euthanasia, we used isoflurane inhalation anesthesia (induction concentration 3%-5%, maintenance concentration 1%-2%) in advance for mice requiring invasive procedures to avoid suffering. However, for mice without preoperative treatment, excessive CO₂ inhalation itself can rapidly lead to loss of consciousness, which meets the ethical requirements of painless euthanasia, so no additional anesthetic was used. All experimental protocols involving live vertebrates were approved by the Experimental Animal Welfare Ethics Committee of Taiyuan Central Hospital (Approval No.: SCXK-2019-0002). All methods were performed in accordance with the national guidelines for laboratory animal facilities and relevant regulations. The reporting of animal studies strictly adheres to the ARRIVE guidelines.

Quantitative real-time reverse transcription PCR

Total RNA was extracted using TRIzol. Complementary DNA was generated by reverse transcription according to the manufacturer’s protocol. Quantitative real-time PCR was performed using Applied Biosystems™ Step One™ Real-Time PCR Systems. The primer sequences used in this experiment are shown in Table 1. Relative transcript levels were corrected by β-actin. Relative quantification was performed according to the ΔΔCt method and the results were expressed in the linear form using the formula 2−ΔΔCt.

Table 1 The primer sequences for qRT-PCR.
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Statistical analysis

The statistical significance was determined using Student’s t-test or one-way ANOVA for comparisons between the experimental groups and the corresponding control groups. Differences were considered statistically significant at *p < 0.05, **p < 0.01.

Results

Lipid metabolism is abnormal in psoriasis

Metabolic reprogramming is crucial for the occurrence and development of psoriasis. However, the ambiguity of matrix-specific metabolic changes in key skin cells (such as mesenchymal stem cells and keratinocytes) and the uncertainty of lipid metabolism regulatory factors have hindered a deeper understanding of its pathogenic mechanism. Therefore, this study addressed these gaps22. As shown in Figure S1, key metabolic pathways—including glycolysis, tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)—are dysregulated in psoriatic cells. To quantify substrate-specific metabolic alterations, we performed oxidative stress tests in psoriatic (P-MSC) vs. normal mesenchymal stem cells (N-MSC) and normal human epidermal keratinocytes (NHEK) using three substrates: Glucose/pyruvate (G/P), Long-chain fatty acids (LCFAs), Glutamine (Q). Basal respiration did not differ between psoriatic and normal cells across all conditions (Fig. 1a, b). Under maximal respiratory demand, P-MSCs showed significantly attenuated responses to: CPT1a inhibition by Etomoxir (LCFAs oxidation), MPC inhibition by UK5099 (G/P oxidation) (Fig. 1a, b; p < 0.05), indicating impaired substrate utilization. Psoriatic NHEKs maintained maximum respiratory capacity comparable to controls (Fig. 1c, d). Transcriptomic analysis of psoriatic lesions revealed significant downregulation (p < 0.05) of lipid metabolism regulators: (PPARG), peroxisome proliferator activated receptor α (PPARA), protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1) peroxisome proliferator-activated receptor γ (PPARG), peroxisome proliferator activated receptor α (PPARA), protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1) and acyl-CoA oxidase 1 (ACOX1) (Figure S2). We further detected the mRNA levels of lipid metabolism-related genes (PPAR, PPARA, PPARD, AMPK, ACACA and ACOX) in psoriasis and normal skin lesions by RT-PCR and found that the expression of these genes was significantly downregulated in psoriasis (Fig. 1e). Overall, these findings reveal the multi-layered metabolic abnormalities of psoriasis, including dysregulation of core metabolic pathways in psoriasis cells, cell type-specific dysfunction, and down-regulation of lipid metabolism regulators. They also clarify the mechanisms of subbase-specific metabolic defects and lipid dysregulation, while providing potential metabolic targets for new therapies.

Fig. 1
figure 1

Lipid metabolism is abnormal in psoriasis. a, b,c, d: Comparing substrate oxidation among N-DMSC, P-DMSC, N-NHEK and P-NHEK cells using LCFAs, XF Glucose Pyruvate, and Glutamine Oxidation Stress Test kits. N-DMSC and P-DMSC (a and b), N-NHEK and P-NHEK (c and d) cells were inoculated on agilent XF24 cell culture plates and grew overnight. Cells were subjected to XF substrate oxidative stress assays by injection of assay medium (control), etomoxir, UK5099, or BPTES, followed by sequential injection of oligomycin, FCCP, and rotenone/antimycin A. e. mRNA expression of PPARg, PPARA, PPARD, AMPK, ACACA and ACOX in psoriasis and normal tissues. f. ADIPOQ expression in psoriatic and normal subjects from GSE 30,999 database analysis (n = 85, P < 0.01). g. RT-qPCR detected the mRNA expression level of ADIPOQ in skin tissues of normal people and patients with psoriasis. n = 3 per group, *p < 0.05, **P < 0.01, ***P < 0.001, ns, not significant, Two-tailed Student’s t-test. Each bar represents the mean ± SEM. All the bars represent the average of three independent experiments.

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ADIPOQ is downregulated in psoriatic lesions

Given the established association between psoriasis and abnormal lipid metabolism, previous studies suggest that the ADIPOQ adipoq may be involved21. The systematic verification of the expression pattern of ADIPOQ in psoriasis tissues/cells, its correlation with psoriasis-related metabolic pathways, and its disease specificity remains crucial for confirming its role as a candidate therapeutic target. To address this issue, we conducted a comprehensive study on the correlation and specificity between ADIPOQ and the pathogenesis of psoriasis by integrating multi-dataset analysis (GSE166388, GSE30999) and experimental verification. Through the GSE166388 dataset, we found a total of 961 DEGs in patients with psoriasis, of which 526 were up-regulated and 435 were down-regulated. DEGs are represented as Volcano (Figure S3a) and heat map (Figure S3b). The differentially expressed genes were then subjected to KEGG pathway analysis.The results showed that DEGs was mainly enriched in fatty acid metabolism and lipogenesis, and was closely related to the progression of psoriasis (Figure S3c). Moreover, GSEA analysis of the expression dataset showed that fatty acid metabolism and adipogenesis were significantly enriched pathways (Figure S3d). These results further suggest the importance of fatty acid metabolism in psoriasis. Moreover, through the analysis of the database GSE30999, we found that ADIPOQ was also downregulated in the psoriatic tissues than the normal tissues (Fig. 1f). Our previous studies have also shown that fatty acid-related gene ADIPOQ is associated with psoriasis, and the expression of ADIPOQ is down-regulated in psoriatic lesions21. Next, we detected ADIPOQ expression in psoriasis and normal MSC by RT-PCR, and found that ADIPOQ expression was significantly down-regulated in psoriasis MSC (Fig. 1g).

Overall, these results confirm that multi-dataset analysis (GSE166388) has identified fatty acid metabolism and adipogenesis as core pathways related to psoriasis. ADIPOQ is continuously downregulated in psoriasis lesions and psoriasis MSCs. It provides mechanism insights for ADIPOQ as a candidate target related to psoriasis-specific metabolism.

High expression of ADIPOQ slowed the lipid metabolism disorders by AMPK - CPT1 signaling pathways

Given that ADIPOQ is a specific and metabolism-related candidate target for psoriasis, to further clarify how ADIPOQ regulates lipid metabolism in MSCs, we combined real-time metabolic flux analysis (XF24) and molecular experiments to systematically characterize the regulatory effect of ADIPOQ on lipid metabolism and related signals in MSCs. Substrate oxidation was measured by assessing changes in oxygen consumption rate (OCR) after adding three inhibitors of mitochondrial substrates (Etomoxir, UK5099, or BPTES) to the MSCs cells. Examination of the basal respiratory parameters for each cell type showed the expected results, showing the same basal ocr in all conditions before the addition of inhibitors (Fig. 2a, b). However, under conditions of maximal respiration, that is, under conditions of high mitochondrial substrate demand, the response to the inhibitors increased significantly, and the response to the different inhibitors was clearly different in the four groups tested. In the N-DMSC-Con and N-DMSC-ADIPOQ group, a response to etomoxir, UK5099 and BPTES is observed. However, compared with N-DMSC-Con, N-DMSC-ADIPOQ shows a larger response to etomoxir, indicating that N-DMSC-ADIPOQ is more dependent on substrate LCFAs oxidation (Fig. 2a). Similarly, the P-DMSC-ADIPOQ group showed a greater gap in maximum percentage after the addition of the etomoxir (CPT-1α inhibitor) relative to the P-DMSC-Con group (Fig. 2b). This suggests that ADIPOQ is significantly dependent on LCFAs oxidation and CPT-1 under conditions of high substrate demand.

Fig. 2
figure 2

ADIPOQ regulates lipid metabolism through AMPK-CPT1 signaling pathway.

ADIPOQ was transfected into DMSC, then the oxidation capacity of the substrate was detected using XF glucose pyruvate, long chain fatty acid and glutamine oxidation stress test kit. Transfected cells of N-DMSC-Con (control group) and N-DMSC-ADIPOQ group (experimental group) (a) and P-DMSC-Con (control group) and P-DMSC-ADIPOQ group (experimental group) (b) were grafted on XF24 cell culture plate overnight. XF substrate oxidative stress tests were performed on cells by adding assay solution (control), Etomoxir, UK5099, or BPTES, and then oligomycin, FCCP, and rotenone/antamycin A in the usual order. c: mRNA expression of ADIPOQ in N-DMSC-Con (control group), N-DMSC-ADIPOQ P-DMSC-Con and P-DMSC-ADIPOQ (experimental group). n = 3 per group (mean ± SEM), *p < 0.05, **P < 0.01, ns, not significant, One-way ANOVA. The contents of MDA (d) and SOD (e) were measured. The expression levels of AMPK and p-AMPK were detected by WB assay (f). The enzyme activity of CPT1 was also detected by CPT1 kit (g). n = 3 per group, *p < 0.05, **P < 0.01, ***P < 0.001, ns, not significant, One-way ANOVA. Each bar represents the mean ± SEM. All the bars represent the average of three independent experiments.

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In order to further verify the lipid oxidation level of ADIPOQ on DMSC, MDA and SOD levels were detected after ADIPOQ transfected with N-DMSC and P-DMSC. Firstly, mRNA levels of ADIPOQ were significantly up-regulated after transfection (Fig. 2c), and MDA and SOD were significantly increased after ADIPOQ was added, especially in P-DMSC-ADIPOQ group (Fig. 2d, e). There is growing evidence that ADIPOQ promotes metabolic processes in multiple target tissues by mediating AMPK activation23. Western blot (WB) results showed that the p-AMPK /AMPK ratio was significantly higher in the P-DMSC-ADIPOQ group than in the other groups (Fig. 2f). Moreover, the enzyme activity of CPT1 was also significantly increased after ADIPOQ was added (Fig. 2g). These findings clarify the mechanism connection between ADIPOQ and lipid metabolism regulation of MSCs, providing direct evidence for the functional role of ADIPOQ in correcting metabolic defects of MSCs in psoriasis.

High expression of ADIPOQ in psoriatic DMSC inhibits keratinocyte proliferation

Given that ADIPOQ has been shown to regulate lipid metabolism in psoriatic dermal-derived mesenchymal stem cells (P-DMSCs), and that the crosstalk between P-DMSCs and keratinocytes (KCs)—a cell type with pathological hyperproliferation in psoriasis—is central to disease progression, we next aimed to investigate whether high ADIPOQ expression in P-DMSCs influences KC proliferation, so as to link ADIPOQ’s function in P-DMSCs to psoriasis’ core cutaneous pathology. We then investigated the effect of high ADIPOQ expression in psoriatic DMSCs on keratinocyte proliferation. Figure 3a shows mesenchymal stem cells co-cultured with NHEKs cells. We found that the survival rate of P-DMSC-ADIPOQ group was significantly higher than that of P-DMSC-Con and N-DMSC-ADIPOQ group (Fig. 3b). 5-Ethynyl-2’-deoxyuridine (EdU) assay (labels cells in the S phase) showed a higher number of EdU positive cells in P-DMSC-ADIPOQ group following co-cultured with NHEKs, when compared with P-DMSC-Con group (Fig. 3c). Furthermore, the proportion of cells in S phase was higher in P-DMSC-ADIPOQ group than P-DMSC-Con group (Fig. 3d). Taken together, these results indicate that high expression of ADIPOQ in psoriatic dermal-derived mesenchymal stem cells stimulate keratinocyte proliferation. This discovery links the regulatory effect of ADIPOQ in P-DMSC to the regulation of KC proliferation, which is a characteristic pathological feature of psoriasis. This provides important evidence that ADIPOQ may intervene in the progression of psoriasis by regulating P-DMSC-KC crosstalk.

Fig. 3
figure 3

ADIPOQ in psoriatic dermal mesenchymal stem cells stimulates keratinocyte proliferation. a: Diagram of DMSC co-culture with NHEK. b, c. After ADIPOQ transfected DMSC was co-cultured with NHEK (control group: N-DMSC-Con (n = 3), experimental group: N-DMSC-ADIPOQ, P-DMSC-Con, P-DMSC-ADIPOQ (n = 3)), the proliferation ability of NHEK cells was detected by EdU and CCK8. d: The changes of S phase and G0G1 phase of NHEK cells after co-culture were further detected by flow cytometry. n = 3 per group, *p < 0.05, **P < 0.01, ns, not significant, One-way ANOVA. Each bar represents the mean ± SEM. All the bars represent the average of three independent experiments.

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ADIPOQ promote IMQ-induced psoriasis through the AMPK-CPT1 pathways

After confirming in vitro that ADIPOQ regulates lipid metabolism and keratinocyte proliferation of psoriasis dermal mesenchymal stem cells (P-DMSCs) through the AMPK-CPT1 pathway, verifying these effects in in vivo psoriasis models is crucial for translating these cellular findings into pathological relevance. Therefore, we used a mouse model of psoriasis-like psoriasis induced by praziquimod (IMQ) and treated it locally with ADIPOQ to evaluate whether the ADIPOQ-mediated AMPK-CPT1 pathway could alleviate psoriasis-like symptoms and regulate key pathological features. It was found that the DMSO group had erythema and scale symptoms after IMQ treatment. However, intraperitoneal administration of ADIPOQ improved the skin condition compared with the DMSO group (Fig. 4a). The severity of skin lesions (erythema, scales) was scored according to PASI on days 1 and 5, which was consistent with the results of Fig. 4a. On day 5, the ADIPOQ group showed lower scores (erythema, scales) in mice than in the DMSO group (Fig. 4b). Histopathological analysis revealed that the epidermis of IMQ-treated mice in DMSO group was thicker than that in ADIPOQ group (Fig. 4c). Then we extracted mRNA from mouse skin tissue, and detected the expression of immune factors IL17A, TNFα, IL23 and IL6 in the skin lesions first, and then detected the expression of ADIPOQ, AMPK and CPT1. The results showed that the expression of immune factor IL17A was significantly increased in IMQ + DMSO mice, and the expression of IL17A was significantly down-regulated after IMQ + ADIPOQ (Fig. 4d), while the expression of AMPK and CPT1 was significantly increased (Fig. 4e). It was further demonstrated that IMQ induced mice had the characteristics of psoriasis, and the addition of ADIPOQ regulated lipid metabolism to reduce the expression of psoriatic immune factors.

Fig. 4
figure 4

ADIPOQ promote IMQ-induced psoriasis through the AMPK-CPT1 pathways.

a: Clinical pictures and skin lesion of the back skin from mice treated with control group DMSO (n = 6) or experimental group ADIPOQ (n = 6) for 5 days. Representative macroscopic images of dorsal skin from mice in each group. Observed macroscopic indicators include: (1) Erythema (intensity and distribution of redness/swelling); (2) Scales (thickness, coverage, and texture of desquamation). The representative images are selected from each group of 6 mice; All animals in each group exhibited phenotypic trends consistent with the shown images. b: Skin lesion of the back skin from mice treated with DMSO or ADIPOQ for 5 days. Quantification of the “Skin Lesion Severity Score,” integrating three parameters (each scored 0–4, with 0 = absent and 4 = most severe): erythema (redness/swelling), scales (desquamation), and epidermal thickness. c: HE staining of the back skin mice treated with DMSO or ADIPOQ for 5 days. Representative dorsal skin sections stained with hematoxylin and eosin (H&E). Observed histological indicators include: (1) Epidermal thickness (measured from the basal layer to the stratum corneum); (2) Inflammatory cell infiltration in the dermis and epidermis (predominantly lymphocytes and neutrophils); (3) Structural changes at the dermal-epidermal junction. (scale bar = 100 μm; enlarged insets, scale bar = 50 μm). d: The mRNA expression of IL17, IL23, TNFα and IL6 in the mice treated with DMSO or ADIPOQ for 5 days. e: The mRNA expression of AMPK and CPT1 in the mice treated with DMSO or ADIPOQ for 5 days. Each bar represents the mean ± SEM; *P < 0.05, **P < 0.01, ns, not significant, Two-tailed Student’s t-test.

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In conclusion, these data link the in vitro mechanism with the in vivo therapeutic potential, indicating that ADIPOQ can alleviate psoriasis-like characteristics by regulating lipid metabolism and inhibiting pro-inflammatory responses, providing preclinical evidence for ADIPOQ as a candidate drug for targeted treatment of psoriasis.

Discussion

Patients with psoriasis are more susceptible to developing concurrent obesity, arterial hypertension, diabetes mellitus, and dyslipidemia, with these associations exhibiting a distinct bidirectional nature28. Owing to chronic inflammation, patients with psoriasis are inherently prone to metabolic disorders; conversely, metabolic disorders can further induce or exacerbate psoriasis by worsening lipid metabolism imbalances. The core pathological basis underlying this bidirectional relationship lies precisely in the regulatory crosstalk of lipid metabolism disorders between localized psoriatic lesions and the systemic metabolic system. Notably, psoriatic lesions exhibit significant lipid metabolism dysregulation, characterized primarily by elevated levels of pro-inflammatory lipids (e.g., arachidonic acid, AA) and reduced levels of anti-inflammatory lipids (e.g., adiponectin). On one hand, AA release from keratinocytes (KCs) in lesional areas is markedly increased; this AA can directly activate T cells—particularly Th17 cells—to secrete IL-17 and TNF-α29. These cytokines not only further stimulate the abnormal proliferation of KCs but also disrupt systemic lipid metabolism via the bloodstream. On the other hand, under conditions of metabolic disturbance (e.g., obesity), visceral adipocytes secrete large quantities of free fatty acids (FFAs), alongside TNF-α, IL-6, and leptin. FFAs can trigger the NF-κB inflammatory pathway in KCs via Toll-like receptor 4 (TLR4) while impairing the lipid membrane of the skin barrier30,47. Additionally, leptin not only promotes Th17 cell differentiation and IL-17 release but also inhibits the secretion of adiponectin (an anti-inflammatory lipid), further disrupting the lipid-inflammatory balance both locally in the skin and systemically. This dual regulatory role renders the function of lipid metabolism in psoriasis increasingly complex. Therefore, further in-depth investigations into the specific regulatory pathways of lipid metabolism are warranted to identify more precise therapeutic targets for psoriasis intervention. By adding three inhibitors of relevant substrates in lipid metabolism, we found that the maximum OCR values of MSC and NHEK in psoriasis were dependent on the metabolism of pyruvate, long-chain fatty acids and glutamine. Interestingly, drugs used to treat metabolic disorders have also been successful in improving skin conditions in patients with psoriasis. Here, we propose that ADIPOQ treatment can alleviate the fatty acid metabolism of psoriatic mesenchymal stem cells, thereby attenuating the proliferation of keratinocytes.

In recent years, many studies have found that low expression of ADIPOQ is a key factor in the development of psoriasis24. Clinical studies in patients with psoriasis have shown that decreased ADIPOQ is the main feature, followed by decreased the level of IL-1725,26. The level of ADIPOQ in the skin tissue of patients with psoriasis is decreased, which aggravates the severity of skin lesions in patients with psoriasis27. In this study, ADIPOQ was reduced in psoriasis patients through the GSE30999 dataset. The results were further validated in skin samples from patients with psoriasis. These results suggest that ADIPOQ expression may be a promising diagnostic biomarker for psoriasis.

ADIPOQ may fulfill its function in psoriasis by activating AMPK pathway31,32. AMPK plays an important role in regulating energy metabolism and fatty acid oxidation, and AMPKα is its main subunit33. AMPKα phosphorylation mediates the synthesis and accumulation of triglycerides by decreasing the action of the transcription factor SREBP-1c. Baicalin may reduce fatty liver disease through AMPK/ACC pathway in animal models with high fat diet34. PPARα is a nuclear receptor that is underexpressed in psoriasis and is capable of transcriptional action on genes involved in fatty acid oxidation, uptake, and inflammation35,36. PPARα can enhance CPT1 transcription when activated by ligand. CPT1, which regulates fatty acid uptake, is the rate-limiting enzyme for mitochondrial fatty acid oxidation, and deficiency of this gene causes liver cells to be unable to oxidize long-chain fatty acids37, resulting in hepatic steatosis. AMPK activation may increase fatty acid metabolism through activation of PPARα38,39 and CPT140. So ADIPOQ, AMPK and CPT1 is the key to lipid metabolism regulating factor, could be psoriasis treatment targets. It is plausible that ADIPOQ activates AMPKα phosphorylation and upregulates CPT1 expression. Also in a mouse model of imiquimote-induced psoriasis, treatment with ADIPOQ also reduced skin lesions and cytokine expression. This suggests that ADIPOQ may increase fatty acid metabolism through the AMPK-CPT1 pathway, thereby reducing the skin lesions symptoms of psoriasis. However, this study has certain limitations that should be acknowledged. First, while the role of ADIPOQ in regulating lipid metabolism and psoriasis pathogenesis was explored, the research lacks long-term follow-up data to verify the stability of ADIPOQ as a diagnostic biomarker for psoriasis or the sustained efficacy of ADIPOQ-based interventions in alleviating psoriatic lesions over time. Second, although the AMPK-CPT1 pathway is proposed as a key mediator of ADIPOQ’s effects, the potential crosstalk between this pathway and other lipid metabolism-related pathways (e.g., PPARα-SREBP-1c axis) in psoriasis remains insufficiently investigated, which may limit a comprehensive understanding of the overall lipid regulatory network in the disease. Third, the validation of ADIPOQ’s therapeutic potential primarily relied on in vitro experiments and imiquimod-induced mouse models; large-scale, multi-center clinical trials are still needed to confirm its safety and effectiveness in human psoriasis patients, especially regarding optimal dosage and potential off-target effects.

Conclusion

In summary, this study confirmed reduced ADIPOQ levels in skin tissue of patients with psoriasis. ADIPOQ is a potent regulator of lipid metabolism, which can promote lipid metabolism in psoriasis and reduce the proliferation of psoriatic keratinocytes and cytokine expression by regulating the AMPK-CPT1 axis. This study suggest that ADIPOQ has diagnostic value in psoriasis. This study provides a new idea for diagnosising and treating psoriasis in the future.