Search Results (254)

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare malignancy in which overexpression of steroidogenic factor-1 (SF-1/NR5A1) and aberrant activation of canonical Wnt/β-catenin signaling are important oncogenic events. However, the extent to which these regulatory axes converge or interact at the transcriptional level remains unclear. We investigated their relationship using bulk transcriptomic and regulatory-network approaches. Methods: Regulatory network inference using RTN/ARACNe was applied to the TCGA-ACC cohort. NR5A1 and β-catenin-associated TCF/LEF regulon activities were evaluated in perturbation datasets and tested for associations with CpG island methylator phenotype (CIMP), overall survival, and gene-level interaction effects. Candidate modulators of NR5A1 activity were assessed using the MINDy algorithm. The effects of cBAF inhibition on NR5A1 regulon activity were also evaluated in H295R and CU-ACC1 cells. Results: NR5A1 knockdown repressed steroidogenic pathways, whereas β-catenin knockdown predominantly suppressed Wnt/β-catenin signaling. In TCGA-ACC, NR5A1 regulon activity was associated with CIMP-high status and overall survival. In contrast, β-catenin-related regulons were not significantly associated with CIMP-high status after adjustment for NR5A1 activity, and no significant multiplicative interaction effects were identified. Fewer than 3% of protein-coding genes showed improved fit in models including NR5A1 × TCF/LEF interaction terms, without enrichment for steroidogenic or Wnt/β-catenin-related pathways. CTNNB1 was identified as a statistically significant but low-ranking positive modulator of NR5A1 activity, whereas CTNNBIP1 was a top-decile negative modulator. cBAF inhibition was associated with NR5A1 regulon repression in both cell models. Conclusions: These findings indicate limited detectable global transcriptional convergence between NR5A1 and canonical β-catenin-related regulons in the evaluated bulk transcriptomic frameworks. Potential relationships between these pathways may depend on more localized, chromatin-dependent, protein-level, or context-specific regulatory mechanisms. NR5A1 regulon activity showed more consistent associations with CIMP-high status and clinical outcome than the β-catenin/TCF-LEF regulons in the evaluated TCGA-ACC models. The modulation patterns associated with CTNNB1 and CTNNBIP1, together with the repression of NR5A1 regulon activity following cBAF inhibition, raise the possibility that NR5A1 acts as a context-dependent regulatory node connecting oncogenic signaling and chromatin-remodeling mechanisms in ACC. These findings support further investigation into the role of chromatin-remodeling complexes in sustaining NR5A1-driven transcriptional programs in ACC. Full article

Since the discovery of truncated mutations of adenomatous polyposis coli proteins in familial adenoma patients in 1991, the mechanism of cytosolic β-catenin regulation has been intensively studied, and now it is very well known that the central role of the canonical Wnt/β-catenin is in colorectal cancer. However, Wnt signaling is very complicated because of the presence of almost 20 Wnt ligand genes, six Frizzled seven-transmembrane receptors, and three LRP co-receptors. In addition, research in the past two decades illuminated the existence of the other Wnt signaling—non-canonical Wnt signaling (Wnt/PCP and Wnt/Ca²⁺ pathways), and an increasing number of studies have shown the potential role of non-canonical Wnt signaling in cancer recently. One of the well-studied Wnt ligands in non-canonical Wnt signaling is Wnt-5a. However, the role of Wnt-5a and non-canonical pathways in cancer is mosaic—i.e., it may involve tumor-promoting or suppressing pathways. In certain cancers, non-canonical Wnt signaling may mainly act as a tumor promoter, yet the results are very controversial in colorectal cancer. Elucidating the role of non-canonical Wnt signaling in colorectal cancer may be very important to further reduce the risk of colorectal cancer, especially in patients who do not carry truncated mutations of adenomatous polyposis coli. In this review, I would like to mainly discuss the apparent controversy surrounding non-canonical Wnt signaling in colorectal cancer, and I would like to point out a few potential reasons contributing to the mysterious roles of Wnt5a-initiated non-canonical signaling in colorectal cancer. Full article

Background and Clinical Significance: Steroid cell tumours of the ovary, not otherwise specified (SCT-NOSs), are rare sex cord–stromal neoplasms with a poorly characterised molecular landscape, in which only exceptional CTNNB1 mutations have so far been reported and no recurrent driver alteration is firmly established. A better characterisation of their molecular spectrum has clinical significance for accurate diagnostic categorisation of ovarian sex cord–stromal tumours and for the identification of potentially targetable pathway alterations in this rare entity. Case Presentation: We report two consecutive SCT-NOSs of the right ovary, retrieved from the archives of the Department of Pathology of the Hôpital Universitaire de Bruxelles and of Curepath. Both underwent comprehensive sex cord–stromal and differential immunohistochemistry and targeted next-generation sequencing on a 168-gene panel with a mean coverage of 2690× (Case 1) and a 17-gene panel (Case 2) (MGI DNBSEQ-T7 for Case 1; Ion GeneStudio S5 for Case 2). A 56-year-old post-menopausal woman (Case 1) and a 50-year-old immunosuppressed woman with a history of renal transplantation and lymphoma (Case 2) both presented with rapidly progressive virilisation. The two right ovarian tumours (20 to 25 mm, no Reinke crystals) displayed an unambiguous sex cord–stromal immunophenotype (α-inhibin, calretinin, SF-1 and Melan-A positive; CD10, WT1, EMA, AE1/AE3 and PAX8 negative), with aberrant nuclear and cytoplasmic β-catenin staining. Sequencing identified a pathogenic CTNNB1 c.133T>C p.(Ser45Pro) variant in Case 1 and a pathogenic CTNNB1 c.95A>T p.(Asp32Val) variant in Case 2, with wild-type FOXL2 in both. Conclusions: Three of the four molecularly characterised CTNNB1-mutated SCT-NOSs converge on the two principal GSK-3β phosphorylation residues of β-catenin, identifying Wnt/β-catenin-pathway dysregulation as a potentially recurrent event and providing additional evidence for the involvement of the Wnt/β-catenin pathway in an emerging molecular subset of SCT-NOS. In a tumour with the canonical sex cord–stromal immunophenotype, an exon 3 CTNNB1 hotspot mutation should not be regarded as evidence against the diagnosis of SCT-NOS and may help define a distinct molecular subset. Full article

Background/Objectives: Chronic venous insufficiency (CVI) is a progressive vascular disorder characterized by sustained venous hypertension leading to structural and functional alterations of the venous wall. Despite its clinical significance, the molecular mechanisms driving venous remodeling remain incompletely understood. The Wnt signaling pathway has emerged as an important regulator of vascular homeostasis and remodeling; however, the expression and coordination of its core components in chronic venous insufficiency (CVI)-affected tissue have not been directly investigated. This study aimed to analyze mRNA expression of FZD2, DVL2, and AXIN1 in great saphenous vein specimens. In addition to gene expression analysis at the individual level, an investigation of co-regulatory networks was also performed to provide insight into Wnt cascade regulation in the varicose and healthy vein tissues. Methods: This single-center, retrospective observational study was conducted on 60 great saphenous vein specimens (32 CVI patients and 28 healthy controls) using re-al-time quantitative PCR. Results: The findings indicate that individual mRNA expression levels of FZD2, DVL2, and AXIN1 remained stable between varicose vein and healthy control tissues, but there were significant changes in transcriptional coordination among these genes in varicose vein tissues, especially enhanced co-expression between AXIN1 and DVL2. All three co-regulated genes exhibited moderate and generally comparable positive correlations in healthy controls: FZD2 with DVL2 (r = 0.526, p-value = 0.0069), DVL2 with AXIN1 (r = 0.486, p-value = 0.0161), and AXIN1 with FZD2 (r = 0.593, p-value = 0.0014). While in varicose vein tissues, DVL2-AXIN1 showed the highest correlation (r = 0.722, p-value < 0.0001), FZD2-DVL2 (r = 0.517, p-value = 0.0096) and AXIN1-FZD2 (r = 0.480, p-value = 0.0084) remained comparable to the healthy tissues. Conclusions: This finding indicates that the involvement of FZD2, DVL2, and AXIN1 in CVI may be driven by altered transcriptional coordination rather than by differential individual gene expression, which may contribute to the molecular pathology of chronic venous insufficiency. Full article

This review summarizes current data on the role of small nucleolar RNAs (snoRNAs) and their host genes (SNHGs) in the development of bladder cancer (BC). It examines snoRNA biogenesis, classical functions (rRNA modification), and non-canonical oncogenic mechanisms, including microRNA sponging, sdRNA production, and protein interactions (EZH2, DNMT3A, hnRNPK). The factors involved in the deregulation of snoRNA/SNHG expression during tumour transformation are described, such as amplifications, epigenetic changes, and transcriptional control (c-Myc, p53). Studies have shown that in BC, the majority of snoRNAs/SNHGs (SNHG1, SNHG3, SNHG6, SNHG13, SCARNA12) act as oncogenes, activating the PI3K/AKT, Wnt/β-catenin, NF-κB, and c-Myc pathways, thereby enhancing proliferation, EMT, invasion, and metastasis. Suppressor molecules (SNHG2/GAS5) are also discussed. The clinical potential of snoRNAs as prognostic signatures (SNORS), diagnostic biomarkers (SNHG1 in urine), and therapeutic targets (e.g., SNHG3) is analyzed. Thus, snoRNAs and SNHGs represent a promising class of molecules for the development of new diagnostic and therapeutic approaches for BC, although further investigation in prospective studies is required. Full article

Pancreatic ductal adenocarcinoma (PDAC) is molecularly characterized by near-universal KRAS mutations and recurrent alterations in TP53, CDKN2A, and SMAD4. Gene fusions are exceptionally rare and have not been established as canonical drivers of PDAC. We report a case of metastatic PDAC harboring an EIF3E::RSPO2 gene fusion in the absence of detectable KRAS or other common driver mutations. A 48-year-old female was diagnosed with stage IV PDAC via endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Comprehensive molecular profiling using the Oncomine Precision Assay GX5 revealed no pathogenic single-nucleotide variants, indels, or copy number variations. However, an EIF3E::RSPO2 fusion, predicted to be a gain-of-function alteration, was identified as the sole genomic alteration. Immunohistochemistry showed retained mismatch repair protein expression and preserved SMAD4. Although RSPO2 fusions have been described in preclinical colorectal cancer models and are well-established activators of the Wnt signaling pathway in this setting, their clinical occurrence in PDAC remains poorly documented. This finding indicates a KRAS wild-type tumor with a potential KRAS-independent oncogenic mechanism that may involve aberrant Wnt/β-catenin signaling and raises the possibility of a rare, biologically distinct PDAC subset. Comprehensive genomic profiling in advanced PDAC may uncover actionable non-canonical drivers with therapeutic implications. Full article

Background/Objectives: Ciliated epithelial change in endometrial lesions is a recognized morphologic finding, but its immunophenotypic correlates and biological significance remain insufficiently defined. We investigated whether endometrial lesions with ciliated epithelial change show reproducible immunohistochemical alterations across benign, premalignant, and malignant diagnostic categories. Methods: We performed a retrospective immunohistochemical study of 315 formalin-fixed paraffin-embedded eutopic uterine endometrial specimens (no endometriotic/ectopic lesions included) collected between 2019 and 2024 and distributed equally across seven diagnostic categories (n = 45 each): normal endometrium, endometrial polyp, hyperplasia with cystic/disordered glands, hyperplasia with crowded glands, atypical hyperplasia/EIN, endometrioid carcinoma, and serous carcinoma. Marker expression was quantified by digital image analysis and compared between lesions with and without ciliated epithelial change, including lesions with ciliated epithelial change showing cytological atypia. Results: Ciliated epithelial change (CEC) was identified in 86/315 cases (27.3%), including 41 cases (13.0%) with atypical CEC. In benign categories, lesions with CEC showed lower E-cadherin expression and higher β-catenin expression, including more frequent nuclear β-catenin localization. In carcinomas, these patterns were not recapitulated and instead showed an opposite or attenuated profile, supporting a context-dependent rather than linear model. Vimentin was consistently reduced in lesions with CEC across diagnostic categories. p53 and CD44 showed heterogeneous findings and were less informative than the adhesion- and phenotype-related markers. Conclusions: Endometrial lesions with CEC show reproducible, context-dependent immunohistochemical alterations, most consistently involving E-cadherin, β-catenin, and vimentin. In particular, nuclear β-catenin reactivity in this setting should not be interpreted as evidence of canonical Wnt-pathway activation in the absence of CTNNB1 sequencing or validated downstream readouts, and the carcinoma findings cannot be assigned to a specific TCGA/ProMisE molecular subgroup using immunohistochemistry alone. The observations should therefore be regarded as exploratory and warrant validation in studies incorporating molecular classification, direct ciliogenesis markers (FOXJ1, acetylated α-tubulin, basal body markers), and outcome data. Full article

Ultraviolet radiation (UVR) exposure accelerates skin aging by disrupting cellular homeostasis and inducing epigenetic changes, such as promoter hypermethylation of key regulatory genes. However, the molecular mechanisms underlying UVR-driven epigenetic silencing remain poorly understood. By integrating high-throughput DNA methylation profiling with co-regulatory network analysis, we identified KIT as a hub gene in a photoaging-associated methylation module. Pathway enrichment further revealed coordinated hypermethylation of the canonical Wnt/β-catenin signaling pathway, establishing the Wnt/KIT axis as a critical epigenetic-signaling nexus in UVR-induced skin fibroblast aging. In immortalized human skin fibroblasts (HSFs), UVR suppressed Wnt signaling, leading to KIT promoter hypermethylation, transcriptional silencing, and premature photoaging. Gain-of-function studies revealed that reversing KIT hypermethylation either via Wnt pathway activation or KIT overexpression effectively mitigated photoaging-associated phenotypes. Crucially, we found that puerarin (PUE), a natural isoflavone, reversed UVR-induced epigenetic silencing by directly interacting with β-catenin, reactivating Wnt signaling, and restoring KIT expression. PUE treatment preserved cellular function in UVR-damaged fibroblasts. These findings establish the Wnt/β-catenin-KIT axis as a critical epigenetic driver of skin aging and highlight puerarin as a promising therapeutic candidate for targeted anti-aging intervention. Full article

Dickkopf-1 (DKK1) is a secreted glycoprotein that traditionally acts as an antagonist of canonical Wnt/β-catenin signaling. Although it functions as a tumor suppressor in some specific biological background and disease stages, growing evidence links DKK1 to tumor progression, immune evasion, and therapy resistance in a variety of multiple malignancies. This review provides a comprehensive bench-to-bedside overview of DKK1 in cancer. We first delineate how DKK1 regulates both Wnt-dependent and Wnt-independent pathways. From a clinical perspective, we evaluate the application potential of DKK1 as a diagnostic and prognostic biomarker. We further discuss the progress of DKK1-targeted interventions, ranging from monoclonal antibodies in clinical trials to next-generation therapeutic modalities. Finally, we discuss the challenges in clinical translation and suggest future directions for DKK1-based precision medicine. In summary, by integrating preclinical insights with current clinical data, this review provides a strategic roadmap for advancing DKK1-targeted therapies in cancer. Full article

Background/Objectives: Chronic Mild Stress (CMS) provokes neuroendocrine dysregulation and oxidative injury that compromise neuronal integrity and plasticity. Disruption of the canonical Wnt/β-catenin signaling pathway has been increasingly linked to stress-induced neurobiological dysfunction. Vitamin D3, a neuroactive hormone with antioxidant and immunomodulatory properties, may exert neuroprotection through modulation of this pathway and attenuation of oxidative damage. The study aims to investigate whether vitamin D3 mitigates CMS-induced alterations in Wnt/β-catenin signaling, oxidative stress markers, and oxidative DNA damage in male Wistar rats. Methods: Thirty-two male Wistar rats were randomly allocated into four groups (n = 8/group): control, CMS only, CMS + vitamin D3 (1000 IU/kg), and CMS + vitamin D3 (10,000 IU/kg). Vitamin D3 was administered intramuscularly three times weekly for 28 days. Hippocampal mRNA expression of Wnt pathway components and brain-derived neurotrophic factor (BDNF) was quantified by RT-qPCR using the 2^−ΔΔCt method. Oxidative stress was evaluated by measuring malondialdehyde, glutathione, superoxide dismutase, and catalase, while DNA damage was assessed via 8-OHdG ELISA. Results: CMS significantly downregulated Wnt1, β-catenin, and Axin2 mRNA expression (p < 0.05) while markedly upregulating GSK-3β (p < 0.001). Expression of BDNF was also reduced (p < 0.05). Biochemically, CMS increased MDA and 8-OHdG levels (both p < 0.001) and decreased glutathione (p < 0.001), superoxide dismutase, and catalase activities (p < 0.05). Vitamin D3 supplementation significantly reversed these transcriptional and biochemical alterations, restoring β-catenin signaling, improving antioxidant defenses, and reducing oxidative and genotoxic damage. Conclusions: Vitamin D3 confers significant neuroprotection under chronic stress by modulating Wnt/β-catenin signaling and attenuating oxidative and DNA damage, thereby enhancing neuronal resilience to prolonged stress exposure. Full article

Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8⁺ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target. Full article

Inflammation occurs throughout the entire process of atherosclerosis. So, reducing the inflammatory response remains one of the main therapeutic strategies for atherosclerosis. Chensinin-1b, a derivative of the natural antimicrobial peptide extracted from the skin secretions of the Rana chensinensis, has been shown to effectively mitigate the occurrence of inflammatory responses. Here, the anti-inflammatory activity of the peptide by suppressing the canonical Wnt/β-catenin signaling pathway was investigated in ox-LDL-induced AS. The results showed that the classical Wnt/β-catenin signaling pathway was activated in ox-LDL-induced THP-1-derived foam cells. The inhibitor of Wnt reduced the release of pro-inflammatory cytokines by downregulating the NF-κB signaling pathway. Cyclooxygenase-2, a target protein of the canonical Wnt/β-catenin signaling pathway, inhibited the phosphorylation of NF-κB. Chensinin-1b and its analogs effectively downregulated the expression of Wnt signaling proteins by inhibiting the nuclear translocation of the key pathway protein β-catenin, resulting in a decrease in COX-2 expression and simultaneously reducing the release of pro-inflammatory cytokines. In summary, our study suggests the potential of chensinin-1b and its analogs as therapeutic agents for AS. Full article

Background and Objectives: Sclerostin or dickkopf-1 (DKK1) inhibits the canonical Wnt/β-catenin signaling pathway, which regulates vascular calcification and may contribute to the development of arterial stiffness. The brachial–ankle pulse wave velocity (baPWV) measures peripheral arterial stiffness (PAS). This study aimed to investigate the correlation between sclerostin and DKK1 levels and PAS in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: Biochemical data and sclerostin and DKK1 levels were analyzed in the fasting blood samples of 125 patients with T2DM. baPWV measurements using the VaSera VS-1000 automatic pulse wave analyzer classified patients with values > 18.0 m/s on either side into the PAS group. Results: Among patients with T2DM, 47 (37.6%) were classified as having PAS. These patients exhibited higher hypertension prevalence (p = 0.002); greater age (p < 0.001); elevated systolic (p < 0.001) and diastolic blood (p = 0.012) pressures; and increased fasting glucose (p = 0.001), glycated hemoglobin (p = 0.008), triglyceride (p = 0.001), blood urea nitrogen (p < 0.001), and creatinine (p = 0.001) levels, urine albumin-to-creatinine ratio (p = 0.039), and C-reactive protein (p = 0.024) and serum sclerostin (p < 0.001) levels, but decreased estimated glomerular filtration rate (p < 0.001). Multivariate logistic regression analysis identified serum sclerostin level (odds ratio, 1.127; 95% confidence interval, 1.058–1.200; p < 0.001) as an independent PAS predictor in patients with T2DM. Serum log-transformed sclerostin levels were positively correlated with left (p = 0.005) and right (p = 0.001) baPWV via Spearman’s rank-order correlation coefficient analysis. Conclusions: Serum sclerostin levels, but not DKK1 levels, are positively correlated with PAS in patients with T2DM. Full article

Skin aging is characterized by fibroblast senescence, extracellular matrix (ECM) degradation, and impaired wound healing, driven by oxidative stress and telomere dysfunction. Here, we investigated the anti-aging effects of a standardized microwave-assisted propolis extract (MAPE) in both H₂O₂-induced and replicative senescence models of human dermal fibroblasts (HDFs). MAPE significantly reduced reactive oxygen species (ROS) accumulation and enhanced antioxidant gene expression (NQO1, GCLM), indicating activation of NRF2-dependent defense pathways. It suppressed senescence markers (CDKN2A, CDKN1A, IL6), decreased SA-β-gal activity, and attenuated inflammaging. Moreover, MAPE inhibited MMP1 expression, restored COL1A1, and improved fibroblast wound closure, thereby maintaining ECM homeostasis. Importantly, MAPE modulated Wnt/β-catenin signaling by upregulating WNT3A and LEF1 while suppressing DKK1, and increased TERT expression, suggesting involvement of telomerase-related regulatory pathways. These effects resembled those of CHIR99021, a canonical Wnt activator, while providing additional antioxidant protection. Together, our findings suggest that MAPE is a propolis-derived bioactive ingredient that counteracts fibroblast senescence through coordinated modulation of NRF2 and Wnt/β-catenin–TERT signaling pathways, supporting its potential as a cosmeceutical ingredient for mitigating skin aging. Full article

Background/Objectives: Psychological stress triggers excessive melanin deposition via neuroendocrine pathways, yet targeted interventions for stress-induced hyperpigmentation remain limited. Salidroside (SAL) exhibits established depigmenting effects in UV-induced models and possesses neuroprotective properties. This study investigated SAL’s efficacy in psychological stress-induced hyperpigmentation and elucidated its underlying mechanisms. Methods: B16F10 melanocytes, C57BL/6J mice, zebrafish, and human foreskin organ cultures were subjected to stress factor (Substance P/cortisol) or α-MSH/IBMX stimulation to model psychological stress-induced and canonical cAMP-driven hyperpigmentation, respectively. Melanin content, tyrosinase activity, melanosome maturation (transmission electron microscopy/HMB45 staining), and melanogenic protein/mRNA expression were assessed. Drug Affinity Responsive Target Stability (DARTS) assays, molecular docking, and SEC23A siRNA knockdown were employed to identify and validate SAL’s molecular target and downstream signaling pathways. Results: SAL dose-dependently reduced melanin content, tyrosinase activity, and TYR/TRP-1/DCT expression in SP/Cort-stimulated melanocytes, exhibiting greater potency (200 μM) than in IBMX-induced models (400 μM). SAL reversed SP/Cort-induced hyperpigmentation in human skin explants, zebrafish, and C57BL/6J mice, and normalized melanosome number/maturation. DARTS and molecular docking identified SEC23A as a direct SAL-binding target. SP/Cort specifically upregulated SEC23A, which SAL suppressed. SAL concurrently activated the SEC23A-p-ERK-MITF axis and inhibited the NK1R-p38-MITF axis in the stress model. SEC23A knockdown potentiated SAL’s anti-melanogenic effects specifically in SP/Cort-stimulated cells. Conversely, in IBMX-induced models, SEC23A remained unchanged, and SAL acted via PKA/CREB, PI3K/AKT, and Wnt/β-catenin pathways. Conclusions: SEC23A is a novel core target in psychological stress-induced hyperpigmentation. SAL selectively binds SEC23A to inhibit stress-induced melanogenesis via dual ERK and p38 MAPK signaling axes, demonstrating etiological specificity distinct from canonical cAMP pathway inhibition. Full article