Skin diseases are characterized by complex pathophysiology and substantial clinical heterogeneity. Their onset and progression involve multiple interconnected processes, including oxidative stress, chronic inflammation, disruption of the skin barrier, microbial dysbiosis, and impaired tissue repair, which often limit the ability of conventional therapies to achieve sustained disease control. Selenium nanoparticles (SeNPs) offer distinct advantages in dermatological treatment by combining the intrinsic biological activities of selenium, such as redox regulation and immunomodulation, with the engineering versatility of nanomaterials. However, therapeutic approaches that rely solely on the inherent bioactivity of SeNPs are increasingly insufficient to address the complexity of disease-associated microenvironments. Accordingly, the development of SeNPs into intelligent, multifunctional therapeutic platforms has emerged as an important direction in this field. Existing reviews have largely focused on the biological functions, preparation methods, or broad biomedical applications of SeNPs, whereas the engineering principles underlying their transition from intrinsically active nanomaterials to intelligent dermatological therapeutic platforms have not been systematically examined. This review therefore focuses on how the intrinsic functions of selenium can be translated, through materials and delivery engineering, into platform-level capabilities relevant to the treatment of skin diseases. By linking disease-specific pathological features and delivery barriers with corresponding design strategies, we propose a mechanism-guided framework for the rational development of SeNP-based dermatological nanomedicines.

Zusammenfassung Hintergrund und Ziele Psoriasis ist eine chronisch‐entzündliche Hauterkrankung, für deren genaue Diagnose und Behandlungsüberwachung nicht‐invasive Diagnosewerkzeuge essenziell sind. Die Multiphotonenmikroskopie (MPM) ermöglicht eine nicht‐invasive Bildgebung der Haut in Echtzeit mit einer Auflösung im Submikrometerbereich. In dieser Studie wurde die diagnostische Genauigkeit der MPM bei Psoriasis und ihre potenzielle Anwendung in der Behandlungskontrolle untersucht. Patienten und Methoden An dieser prospektiven Beobachtungsstudie nahmen 34 Patienten mit Psoriasis teil. Die Studie umfasste drei Teile: (1) die Analyse der Bildgebungsmerkmale läsionaler und nicht‐läsionaler Haut mittels MPM (Transcend Vivoscope); (2) die Bewertung der diagnostischen Leistungsfähigkeit von MPM‐Parametern im Vergleich zur konfokalen Reflexionsmikroskopie (RCM); und (3) die prospektive Überwachung von 24 Patienten, die 8 Wochen lang (T0/T1/T2) mit Benvitimod (Tapinarof)‐Creme behandelt wurden. Ergebnisse Die MPM erkannte Psoriasis‐Merkmale (einschließlich Hyperkeratose, Parakeratose, fehlendes Stratum granulosum, vergrößerter Kerndurchmesser und fehlende helle Umrandung) mit vergleichbarer diagnostischer Effizienz wie die RCM (AUC = 0,838, p < 0,001 vs. 0,824, p < 0,001). Die psoriatischen Läsionen zeigten im Vergleich zu gesunder Haut eine signifikante perinukleäre Fluoreszenzanreicherung (p < 0,001). Alle Bildgebungsmerkmale verbesserten sich nach 8‐wöchiger Behandlung signifikant (p < 0,001). Die PASI/TLS‐Werte zeigten Korrelationen mit der Dicke der Epidermis (r = 0,403/0,492, p < 0,001), mit dem Kerndurchmesser (r = 0,4/0,375, p < 0,001) und mit der Fluoreszenzintensität (r = –0,419/–0,492, p < 0,001). Schlussfolgerungen Die MPM ist eine neuartige und nicht‐invasive Bildgebungstechnik zur Beurteilung und Behandlungsüberwachung von Psoriasis.

Pachyonychia congenita tarda (PCT) is a rare late-onset variant of pachyonychia congenita (PC), with its nosological status remaining controversial due to limited molecular confirmation in adult-onset cases. We report a 57-year-old Chinese woman who presented with a four-year history of progressive, painful thickening of all 20 nails, accompanied by mild palmoplantar keratoderma. Repeated mycological examinations were negative, and no clinical improvement was observed after prolonged antifungal therapy. Familial segregation analysis could not be performed because biological samples from relatives were unavailable, and the patient reported no known affected relatives. Whole-exome sequencing (WES), followed by Sanger confirmation, identified a heterozygous missense variant in KRT6A (c.661C>A, p.Leu221Ile), predicted to be pathogenic. Notably, the mutation is located outside the highly conserved helix boundary motifs (HBM), in contrast to classic PC-associated variants that typically present in early childhood. The patient's phenotype was relatively mild and characterized by isolated late-onset nail dystrophy. To our knowledge, this case represents the latest reported onset of PCT, occurring at 53 years of age, and provides molecular evidence supporting PCT as a distinct clinical entity rather than a misdiagnosis of other keratinization disorders. We further propose that mutations outside HBM regions, combined with conservative amino acid substitutions, may preserve partial keratin function and delay disease manifestation until later in life. In conclusion, PCT should be considered in the differential diagnosis of treatment-resistant onychomycosis, particularly in older adults, and WES may serve as a valuable tool for accurate diagnosis.

Background:Skin is the largest organ of the human body. It continuously encounters environmental toxicants, including airborne pollutants, which may induce many skin disorders, such as psoriasis. However, evidence on the association between airborne pollutants and psoriasis prevalence in China remains limited. Methods:We used nationwide inpatient diagnostic data on psoriasis from 2021 to 2023, encompassing 149 744 cases across 31 provinces, municipalities, and autonomous regions in China, along with corresponding air pollution data. We analysed the spatial distribution and clustering patterns of psoriasis using the spatial autocorrelation analysis. We employed Pearson correlation analysis and Geodetector to explore the spatial heterogeneity of psoriasis and its association with airborne pollutants at the provincial level. We assessed the explanatory power of individual airborne pollutants and their combined effects on psoriasis prevalence. Results:Pearson correlation analysis revealed that PM10 (r = 0.604), PM2.5 (r = 0.429), air quality index (AQI) (r = 0.542), and NO2 (r = 0.476) have significant positive correlations with psoriasis prevalence. Psoriasis and its subtypes exhibited significant spatial heterogeneity and diverse clustering patterns across regions. Geodetector identified PM10 (q = 0.357; P = 0.000), AQI (q = 0.315; P = 0.000), and O3 (q = 0.264; P = 0.000) as key contributors to this spatial heterogeneity. Interactive detection analysis further revealed that the combined effects of specific pollutant pairs, including PM2.5 and SO2 (q = 0.790), PM10 and SO2 (q = 0.727), as well as O3 and SO2 (q = 0.704), played a pivotal role in explaining the prevalence of psoriasis. The other combinations also showed an important impact on psoriasis subtypes, including psoriasis vulgaris (PM2.5 and SO2) (q = 0.792), psoriasis erythematous (PM2.5 and SO2) (q = 0.852), psoriatic arthritis (PM10 and O3) (q = 0.840), and nail psoriasis (PM10 and O3) (q = 0.789). Conclusions:The airborne pollutants influence psoriasis prevalence and its subtypes. With the largest global study of the Asian population, we provide novel insights into the impact of air pollution on psoriasis, guiding future public health policies and clinical interventions.

Background:Accurate quantification of skin color is essential for dermatologic research and clinical practice. Conventional methods rely on specialized equipment, trained operators, and high costs. Smartphone-based technologies provide a promising alternative for accessible skin color assessment. Objective:To evaluate the reliability and validity of the smartphone-based skin colorimeter application, You Look Good Today (YLGTD), for facial skin color assessment compared with two validated devices, VISIA and DermaLab Combo. Methods:A total of 105 Chinese participants with healthy facial skin were enrolled. Cheek skin color measurements were obtained using YLGTD (user self-assessment and physician measurement modes), VISIA, and DermaLab Combo. Inter-rater reliability between YLGTD measurement modes was assessed using intraclass correlation coefficients (ICC) and Bland-Altman analysis. Criterion validity was evaluated using Pearson's correlation coefficients between YLGTD measurements and the reference devices. Results:YLGTD demonstrated excellent inter-rater reliability across all parameters (ICC: 0.85-0.95). Bland-Altman analysis showed small biases between the two measurement modes for the L, a, and b (-0.05, 0.18, and -0.99, respectively). For criterion validity, YLGTD in user mode showed strong correlations with DermaLab Combo for L* (r = 0.71), individual typology angle (ITA°, r = -0.81), and chroma (C*, r = 0.78), and moderate correlations for b* (r = 0.59) and hue (h°, r = 0.57). Correlations were consistently stronger in physician mode (L*: r = 0.77; b*: r = 0.75; C*: r = 0.84; ITA°: r = -0.87). VISIA showed a stronger correlation for a* (r = 0.55) but weaker correlations for L* (r = 0.56) and ITA° (r = -0.68) compared with YLGTD. Conclusion:The smartphone-based application YLGTD demonstrated excellent reliability and acceptable validity for facial skin color assessment, particularly for pigmentation-related parameters. Its standardized measurement workflow and integrated algorithms enable consistent skin color evaluation across devices and real-world conditions, providing a convenient and cost-effective approach for objective skin color assessment.

Dysbiosis of the skin microbiome, characterised by Staphylococcus aureus overgrowth and imbalance of commensals such as Staphylococcus epidermidis (S. epidermidis), is closely associated with atopic dermatitis (AD). However, the therapeutic relevance of defined S. epidermidis-associated indole metabolite, especially indole-3-acetic acid (IAA), in AD-like inflammation remains incompletely characterised. Here, we investigated the role of IAA, a tryptophan-derived metabolite enriched in the culture supernatant of the tested S. epidermidis strain, in AD-like inflammation. Public transcriptomic analyses suggested impaired AHR-associated and tryptophan-metabolism signatures in AD skin, particularly in lesional skin, while human metagenomic data indicated AD-associated staphylococcal alterations. Targeted metabolomics identified IAA as an enriched indole metabolite in S. epidermidis culture supernatant. In an MC903-induced AD-like mouse model, cutaneous IAA levels and S. epidermidis abundance were reduced. Topical IAA attenuated AD-like phenotypes, improved barrier-related proteins and reduced inflammatory indices. These protective effects were diminished by the AHR antagonist CH223191. Molecular docking predicted a possible interaction between IAA and AHR, and in vitro assays showed that IAA modulated keratinocyte AHR-associated inflammatory and barrier-related responses. Together, our findings support IAA as a microbiome-associated postbiotic candidate for AD management, at least partly through AHR-associated signalling.

In a cohort of 3612 atopic dermatitis patient-partner dyads, we evaluated agreement between clinician-rated severity (SCORAD) and independent patient- and partner-reported symptom severity (POEM/partner-POEM), and explored links with short-term response (EASI 90 at week 20) and work functioning. Patients and partners reported symptom severity very similarly, yet discordance with SCORAD was concentrated in moderate disease; higher baseline agreement was associated with better short-term response. Partner burden - including sleep loss and depressive symptoms - rose with clinician-rated severity and correlated with work limitation in employed dyads.

BACKGROUND AND OBJECTIVES:Psoriasis is a chronic inflammatory skin disease, and noninvasive diagnostic tools are essential for accurate diagnosis and treatment monitoring. Multiphoton microscopy (MPM) enables real-time, noninvasive skin imaging with submicron resolution. This study evaluated the diagnostic accuracy of MPM in psoriasis and its potential application in therapeutic monitoring. PATIENTS AND METHODS:This prospective observational study enrolled 34 patients with psoriasis. It comprised three parts: (1) analysis of imaging features of lesional and nonlesional skin using multiphoton microscopy (MPM; Transcend Vivoscope); (2) evaluation of the diagnostic performance of MPM parameters compared with reflectance confocal microscopy (RCM); and (3) prospective monitoring of 24 patients treated with Benvitimod (Tapinarof) cream for 8 weeks (T0/T1/T2). RESULTS:MPM detected psoriasis characteristics (including hyperkeratosis, parakeratosis, an absent stratum granulosum, enlarged nucleus diameter, and absent bright rimming) with comparable diagnostic efficiency to RCM (AUC = 0.838, p < 0.001 vs. 0.824, p < 0.001). Psoriatic lesions showed significant perinuclear fluorescence accumulation compared to healthy skin (p < 0.001). All imaging features improved significantly after 8 weeks of treatment (p < 0.001). PASI/TLS scores showed correlations with the epidermal thickness (r = 0.403/0.492, p < 0.001), nuclear diameter (r = 0.4/0.375, p < 0.001), and fluorescence intensity (r = -0.419/-0.492, p < 0.001). CONCLUSIONS:MPM is a novel and non-invasive imaging technique for psoriasis evaluation and treatment monitoring.

Herpes zoster (HZ), caused by varicella-zoster virus reactivation, is characterized by painful dermatomal eruptions. Systemic metabolic alterations during acute infection remain incompletely defined. In this exploratory case-control study, serum samples from 47 acute HZ patients and 30 healthy controls were analyzed using untargeted ultra-high-performance liquid chromatography-high-resolution mass spectrometry. Differential metabolic features were identified using models adjusted for age and analytical batch (p < 0.05; FC ≥ 1.2 or ≤ 0.83). Pathway enrichment was explored by over-representation analysis. A nested cross-validated LASSO-logistic regression model incorporating selected metabolites, age, and batch was constructed to assess exploratory internal discrimination. Thirty-eight differential metabolic features were identified, involving nucleoside, amino acid, lipid, and energy metabolism. Pyrimidine-related and amino acid-related pathways appeared among the leading nominal pathways. A four-metabolite panel (Uridine/Pseudouridine, Uracil, 2-Pyrrolidinone, and L-Methionine), combined with age and batch, yielded an internal cross-validated AUC of 0.91 (95% CI: 0.8369-0.9688). These four core metabolic features retained the same directions of change in the age-overlap sensitivity cohort, with nucleoside-related features elevated and L-Methionine decreased in HZ patients. Acute HZ is associated with alterations in serum metabolic features, particularly involving nucleoside-related and amino acid-related signals. These exploratory findings provide a metabolic overview of acute HZ and require validation in independent, age-matched cohorts.

AIMS:This study aimed to elucidate the role of oligoadenylate synthase-like protein (OASL) as a pivotal regulator integrating keratinocyte hyperproliferation, inflammation, and lipid metabolic dysregulation in psoriasis pathogenesis. MATERIALS AND METHODS:Clinical analyses compared epidermal OASL expression levels between psoriasis patients and healthy individuals. Functional studies in HaCaT cells employed OASL knockdown and overexpression to assess effects on proliferation, inflammatory responses, and lipid metabolism. The JAK1-STAT1-OASL regulatory axis was investigated using the JAK1 inhibitor Upadacitinib. The natural flavonoid Astilbin was screened as an OASL inhibitor, and its therapeutic efficacy was evaluated in imiquimod-induced psoriatic mice. KEY FINDINGS:OASL was significantly upregulated in psoriatic epidermis. Knockdown of OASL suppressed keratinocyte proliferation and inflammation, while its overexpression promoted hyperproliferation, inflammation, and lipid metabolic dysregulation via p38 MAPK pathway activation. Mechanistically, Upadacitinib reduced OASL expression by inhibiting STAT1, confirming the JAK1-STAT1-OASL axis. Astilbin markedly alleviated imiquimod-induced psoriasiform dermatitis in mice. SIGNIFICANCE:This study reveals OASL's pivotal regulatory role in psoriasis and its associated pathways, providing novel therapeutic targets and a potential natural drug candidate. These findings establish a theoretical foundation for developing multi-targeted strategies against psoriasis.

To investigate the role of lncRNA PVT1 in modulating CD4+ T cell subsets and its contribution to systemic lupus erythematosus (SLE) pathogenesis in human patients and MRL/lpr mice. Measured PVT1 and miR-30e-5p expression in SLE patients (n = 65) and healthy controls (HCs) using qRT-PCR. Analyzed Th1/Th2/Th17/Treg cell frequencies by flow cytometry and cytokine levels (IL-2, IL-4, IL-6, IL-17, TGF-β) via ELISA. Constructed lentiviral vectors to silence (SLE + si-Pvt1) or overexpress Pvt1 (SLE + lenti-Pvt1) in MRL/lpr mice (n = 40). PVT1 was upregulated (p = 0.0488) and miR-30e-5p downregulated (p = 0.0095) in SLE patients. Th2 (p = 0.0165) and Th17 (p = 0.0017) cells exhibited a significant increase, while Th1 and Treg cells decreased. Pvt1 silencing reversed SLE phenotypes, increasing Th1 and Treg cells, reducing Th2 and Th17 cells, restoring IL-2 and TGF-β levels and reducing levels of IL-6 and IL-17. Overexpression of Pvt1 exacerbated disease severity. Pvt1 acted as a ceRNA to sponge miR-30e-5p, modulating T-bet/GATA3/RORγt/Foxp3 expression. PVT1 dysregulation disrupts CD4+ T cell homeostasis in SLE. Targeting the PVT1/miR-30e-5p axis may restore immune balance and represent a novel therapeutic strategy.

The prevalence of rosacea is high, while the drug options remain limited. Mendelian randomization (MR) is an effective way to prioritize plasma proteins as novel drug targets based on their causal effects on rosacea. The plasma proteins were categorized into different levels of drug targets by the MR and Bayesian colocalization analysis. Their genetic and protein expression was investigated using an RNA sequencing dataset and experiments in vitro and in vivo. MR and colocalization identified Granzyme K (GZMK) as a drug target, whose expression increased in the affected samples. A novel mouse model of rosacea was established by GZMK, mimicking rosacea-like symptoms both in vitro and in vivo. GZMK also promoted cell proliferation and inflammatory factors (including IL-1β, IL-6, and TNFα) production in fibroblasts through activating the NF-κB pathway in vitro. Our research identified a novel protein involved in rosacea pathogenesis, elucidated the underlying mechanisms, and advanced the development of potential rosacea treatments.

Skin diseases impose a substantial burden on global healthcare systems, driven by their high prevalence (affecting up to 70

Vitiligo is a chronic, disfiguring disease associated with autoimmune comorbidities and psychosocial burdens, although comprehensive Chinese population data remain limited. This study systematically characterizes the clinical and psychosocial profiles of treatment-seeking patients with vitiligo, addressing gaps in understanding disease severity, comorbidities, and mental health impacts to guide integrated management approaches. A cross-sectional analysis of 5227 Chinese patients with vitiligo after unsatisfactory conventional therapy was conducted. Among the 5227 patients with vitiligo, nonsegmental vitiligo (88.7%) predominated, with 73.2% in progressive stage. Family history was reported in 13.5%, and comorbidities (primarily thyroid disorders, 10.9%) occurred in 21.2%. Most patients (62%) developed vitiligo before the age of 30 years. All received prior treatments (79% received ≥2 therapies), and 94.2% had visible-area lesions (face/neck/hands), with ∼80% showing complete depigmentation. Severe vitiligo was significantly associated with male sex (adjusted OR [aOR] = 2.17), disease duration >10 years (aOR = 20.56), and nonsegmental subtype (aOR = 12.31). QOL impairment was observed in the following characteristics: female sex (aOR = 1.87), severe vitiligo (aOR = 1.66), depression (aOR = 1.81), low self-esteem (aOR = 2.83), and hopelessness (aOR = 2.59). Chinese patients with vitiligo face multidimensional burdens-chronicity, visible-area depigmentation, comorbidities, and psychological distress-exacerbated by fragmented treatments. Findings underscore the need for integrated management models combining dermatological, psychological, and systemic interventions beyond depigmentation-focused therapies.

To the Editor: Atopic dermatitis (AD) is a chronic inflammatory skin condition marked by recurrent eczematous lesions and intense pruritus, affecting approximately 15–20% of children and up to 10% of adults worldwide.[1] The presence of AD significantly impairs patient quality of life and imposes substantial economic burdens on society. In recent years, the potential link between AD and lymphoma has attracted considerable attention from researchers and clinicians. Lymphoma, a malignancy of the lymphatic system, poses significant health risks due to its high mortality potential.[2] However, observational studies investigating the potential correlation between AD and lymphoma have yielded inconsistent results. Consequently, the association between AD and lymphoma remains controversial and warrants further investigation. To assess the causal links between AD and lymphoma, we initially employed two-sample bidirectional Mendelian randomization (MR). Subsequently, metabolome-wide MR analyses were conducted to evaluate the roles of blood and urine metabolites in mediating these causal relationships. Additionally, we integrated proteome-wide MR, summary-data-based MR (SMR), and colocalization analyses to identify the causal relationships between plasma proteins and the risk of AD and lymphoma, aiming to discover new druggable targets. This study utilized publicly available summary-level data [Supplementary Table 1, https://links.lww.com/CM9/C273]. All studies received ethical approval from the relevant institutional review boards, with informed consent obtained from all participants. Detailed materials and methods are provided in Section "Material and Methods" in Supplementary Material, https://links.lww.com/CM9/C271. The two-sample MR analyses indicated that AD was associated with an increased risk of NK/T cell lymphoma (NKTL) in both the UK Biobank (UKB) and FinnGen cohorts. This association remained statistically significant following meta-analysis and Bonferroni correction [Figure 1A]. A positive association between AD and the risk of mantle cell lymphoma (MCL) was suggested in the FinnGen cohort, but not in UKB cohort. However, this association reached statistical significance after meta-analysis and Bonferroni correction. No evidence was found supporting a correlation between AD and the risk of developing Hodgkin lymphoma, follicular lymphoma, diffuse large B cell lymphoma, or marginal zone B cell lymphoma [Supplementary Tables 2 and 3, https://links.lww.com/CM9/C273]. The reverse MR analyses suggested that lymphoma was not associated with an elevated risk of AD.Figure 1: Research diagram and summary of study. (A) Meta-analyses reveal the associations between AD and the risk of NKTL and MCL. (B). Metabolome-wide MR analyses reveal blood and urine metabolites associated with the risk of AD, NKTL, and MCL. (C). Workflow of conducting proteome-wide MR analysis using pQTL data from deCODE and UKB-PPP studies, supplemented by SMR and colocalization analysis, to identify associations between plasma proteins, AD, NKTL, and MCL. (D). Manhattan plot displaying PheWAS analysis results for ERN1, FAS, PRDX6, and PSMD5 in the UKB-SAIGE study. The Y-axis represents the logarithm of the P-values. The dotted line indicates the threshold for suggestive statistical significance (P <0.05). The top six associations are labeled by name. The 783 phenotypes from the UKB-SAIGE study are clustered into 17 groups shown in X-axis: 1 circulatory system; 2 congenital anormalies; 3 dermatologic; 4 digestive; 5 endocrine/metabolic; 6 genitourinary; 7 hematopoietic; 8 infectious diseases; 9 injuries & poisonings; 10 mental disorders; 11 musculoskeletal; 12 neoplasms; 13 neurological; 14 pregnancy complications; 15 respiratory; 16 sense organs; 17 other symptoms. An interactive 3D illustration is provided in Supplementary Figure 1, https://links.lww.com/CM9/C272 (electronic version only). AD: Atopic dermatitis; AST: Aspartate aminotransferase; CEs: Cholesterol esters; CHO: Cholesterol; coloc: colocalization; ERN1: Endoplasmic reticulum to nucleus signaling 1; Finn: FinnGen study; MCL: Mantle cell lymphoma; MR: Mendelian randomization; NKTL: NK/T cell lymphoma; PheWAS: Phenome-wide association studies; pQTL: Protein quantitative trait locus; PRDX6: Peroxiredoxin 6; PSMD5: Proteasome 26S Subunit Non-ATPase 5; SMR: Summary-data-based Mendelian randomization; UKB: UK Biobank study.The metabolome-wide MR analyses identified 9 metabolites associated with the risk of developing AD in the FinnGen cohort and 11 metabolites in the UKB cohort [Supplementary Tables 4 and 5, https://links.lww.com/CM9/C273]. Meta-analysis of the FinnGen and UKB datasets identified six metabolites that may influence the risk of developing AD [Figure 1B]. The MR analyses also suggested that AD was associated with a slight decrease in albumin and insulin-like growth factor 1 (IGF-1), and a moderate increase in cholesteryl ester levels in chylomicrons and extremely large very low-density lipoprotein (VLDL) particles after meta-analysis [Supplementary Tables 4 and 5, https://links.lww.com/CM9/C273]. Furthermore, the MR analyses indicated that elevated levels of apolipoprotein A (ApoA) were associated with a decreased risk of developing NKTL, while sphingomyelins, cholesterol, and its derivatives were associated with an increased risk of developing MCL [Figure 1B and Supplementary Tables 6–9, https://links.lww.com/CM9/C273]. Next, we conducted proteome-wide MR, SMR, and colocalization analyses to elucidate the association between circulating proteins and the risk of AD, NKTL, and MCL. These analyses identified 11 proteins associated with the risk of AD, 5 proteins associated with the risk of NKTL, and 10 proteins associated with the risk of MCL [Figure 1C and Supplementary Tables 10–13, https://links.lww.com/CM9/C274]. Both proteome-wide MR and SMR analyses indicated that Endoplasmic Reticulum to Nucleus Signaling 1 (ERN1) and Proteasome 26S Subunit Non-ATPase 5 (PSMD5) were associated with the progression of both AD and NKTL. Additionally, proteome-wide MR analyses from both the deCODE and UKB-PPP studies, as well as the SMR analysis, implicated Peroxiredoxin 6 (PRDX6) in the progression of AD and Fas Cell Surface Death Receptor (FAS) in the pathogenesis of MCL. Notably, the association between ERN1, PSMD5, PRDX6, and FAS with AD and/or lymphoma were corroborated by multiple analyses, highlighting them as potential targets for drug repurposing. Given that the associations of these proteins with their respective diseases were corroborated by multiple screening methods and their relevance as drug targets, these four proteins were selected for phenome-wide association studies (PheWAS) to evaluate potential safety implications. MR analyses revealed that ERN1 was primarily associated with digestive diseases and neoplasms, FAS was predominantly associated with neoplasms and melanomas of the skin, PRDX6 had a strong association with epilepsy, and PSMD5 demonstrated significant associations with respiratory and skeletal diseases [Figure 1D and Supplementary Table 14, https://links.lww.com/CM9/C274]. An interactive 3D illustration is provided [Supplementary Figure 1, https://links.lww.com/CM9/C272]. Aligned with previous observational studies,[3,4] our study suggests that AD is associated with an increased overall risk of lymphoma, specifically NKTL and MCL. Metabolome-wide MR analyses indicated that docosahexaenoic acid (DHA) and histidine are associated with a reduced risk of AD, consistent with their known pharmacological and nutritional benefits. AD led to alterations in cholesterol accumulation, which elevated the risk of lymphomas.[5] Our analysis further identified an association between sphingomyelins and an increased risk of developing MCL, aligning with the recognized role of sphingomyelins in cancer initiation, growth, and immune evasion.[6] Overall, alterations in lipid metabolism, particularly cholesterol, may bridge the causal links between AD and lymphoma. Proteome-wide MR using pQTL data from the deCODE and UKB-PPP studies, aided by SMR and colocalization analyses, identified distinct plasma proteins associated with AD, NKTL, and MCL. However, shared proteins between these diseases were also identified. Furthermore, JAK-STAT signaling pathway and cytokine dysregulation may drive both conditions.[7] Studies have also demonstrated that inflammatory and immune-related genetic loci exhibit pleiotropy, affecting multiple diseases.[8] These findings, together with our study, further corroborate the genetic correlations between AD and lymphoma, underscoring the importance of conducting lymphoma screening in patients with AD to potentially improve early detection and intervention strategies. By leveraging multi-omics data and employing various analytical tools, our research provides insights into the intricate relationship between AD and lymphomas, ultimately guiding the development of targeted interventions and improving risk stratification and personalized patient management. Funding This study was supported by grants from the National Key R&D Program of China (Nos. 2022YFC3602002 and 2024YFF0507404), and National High Level Hospital Clinical Research Funding (Nos. 2022-NHLHCRF-LX-02-03 and 2023-NHLHCRF-YXHZ-ZRZD-06).