Daniela Kovacs

Pathological aggregation of α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), but increasing evidence indicates that αSyn deposits extend beyond the central nervous system to peripheral tissues, including the skin. In PD patients, cutaneous αSyn accumulation has been associated with seborrheic dermatitis (SD), a chronic inflammatory condition linked to sebocyte dysfunction and altered sebum production. Marked differences in sebum composition between PD patients and healthy controls have been described. We aimed to investigate whether pathological αSyn could contribute to dysregulated sebum production and composition by assessing key markers of sebocyte differentiation and lipogenesis in human sebaceous gland cells and skin biopsies from PD patients (n = 5) and matched controls (n = 5) without clinically recorded SD. O-αSyn exposure of immortalized sebaceous gland cells (SZ95) altered the transcriptional programs related to sebocyte differentiation, inflammation, metabolism, and lipogenesis. Consistently, protein markers of mid-to-late sebocyte differentiation were increased. Upregulation of PLIN2, together with elevated PPARγ, SREBP1, SCD1, and FADS2, indicated progression toward a mature and lipid-producing phenotype characterized by enhanced accumulation of neutral lipids within lipid droplets. Lipidomic profiling revealed remodeling of multiple lipid classes, with increases in triglycerides, ceramides, and selected phospholipids. Increased expression of PLIN2 and PPARγ was also observed in sebaceous glands from PD skin biopsies compared to controls. Collectively, our findings indicate that O-αSyn exposure is associated with molecular changes consistent with altered sebocyte differentiation and lipid remodeling. These results support a potential association between αSyn and lipid dysregulation in sebocytes and suggest that these cells may represent unrecognized peripheral targets of αSyn.

Melanoma is the deadliest form of skin cancer, characterized by high metastatic potential and intrinsic heterogeneity. In addition to genetic mutations such as BRAF^V600E^ and NRAS, lipid metabolic reprogramming has emerged as a critical factor in tumor progression and therapy resistance. Lipid metabolism supports melanoma cell survival, phenotypic switching, immune evasion, and resistance to targeted therapies and immunotherapy, while also modulating susceptibility to ferroptosis. This review summarizes current knowledge on lipid dysregulation in melanoma, highlighting alterations in fatty acid synthesis, desaturation, uptake, storage, and oxidation, as well as changes in phospholipids, sphingolipids, cholesterol, and bioactive lipid mediators. These lipid pathways are tightly regulated by oncogenic signaling networks, including MAPK and PI3K–AKT–mTOR pathways, and are influenced by tumor microenvironmental stressors such as hypoxia and nutrient limitation. Advances in lipidomics technologies, particularly mass spectrometry-based approaches, have enabled comprehensive profiling of lipid alterations at bulk, spatial, and single-cell levels, offering new opportunities for biomarker discovery and therapeutic stratification. Targeting lipid metabolic vulnerabilities represents a promising strategy to improve melanoma diagnosis, prognosis, and treatment efficacy.

Cutaneous melanoma is a highly aggressive skin cancer prone to relapse and metastasis. Surgery is often curative when combined with early screening and prevention. However, in recurrent or advanced disease, the development of new targeted and immune therapies has demonstrated promising clinical outcomes, although the acquisition of resistance limits their effectiveness. Thus, new therapeutic approaches are needed. Emerging data indicate that the Hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly reactivated in melanoma and may represent a promising therapeutic target. Here, we demonstrate its chronic up-modulation in a panel of patient-derived cell lines and, by investigating the underlying molecular mechanisms, we excluded mutations in the principal components of the pathway. We observed reduced PTCH1 and SUFU repressors expression and GLI2 upregulation as common melanoma features. At the same time, copious SHH release, the principal PTCH1 ligand, evidenced autocrine Hh signaling activation. Consistently, a tendency of greater level of this factor resulted higher in the blood of patients compared to controls, confirming the relevance of ligand-dependent trigger in melanoma. The therapeutic potential of inhibiting the Hh pathway is highlighted by the reduced proliferation and migration observed in the presence of clinically approved pharmacological Hh antagonists. Profiling inflammatory mediators revealed significant modulation upon treatment with SMO inhibitors, possibly affecting chemotactic and immune functions. Collectively, these findings provide deeper insight into the role of the Hh pathway in melanoma and support the potential repurposing of Hh inhibitors as therapeutic agents for melanoma.

The Tumour Microenvironment (TME) is pivotal for melanoma progression and contributes to therapy resistance. While dermal cell involvement is well established, the role of epidermal cells remains less defined. To explore the contribution of Normal Human Keratinocytes (NHKs) to melanoma biology, we investigated the modification of gene and protein expression of NHKs exposed to melanoma-conditioned medium or maintained in a co-culture system. The analysis focused on pathways related to proliferation, inflammation, Extracellular Matrix (ECM) remodelling, and cell adhesion. Due to the well-documented melanoma–fibroblast crosstalk, Normal Human Fibroblasts (NHFs) and Cancer-Associated Fibroblasts (CAFs) were used as comparative references. Keratinocyte gene expression changes under the influence of melanoma secretome only partially overlapped with those of NHFs and CAFs, indicating cell-type-specific responses. Exposure to melanoma-conditioned medium induced the upregulation of bFGF, CXCL-16, TIMP-2, and E-cadherin in NHKs, alongside downregulating TGF-β and MMP-9. Although bFGF is a recognized pro-tumorigenic factor, the modulation of CXCL-16, TIMP-2, and TGF-β may reflect a protective response. Notably, under co-culture conditions, NHKs exhibited a pronounced pro-inflammatory and ECM-remodelling phenotype, characterized by elevated production of cytokines (IL-1α, IL-1β, and IL-8) and ECM-degrading enzymes (MMP-7, 9, 12, and 13), indicative of a pro-tumoral feature. Collectively, these findings underscore an active role for NHKs in melanoma initiation and progression.

Skin pigmentation results from complex cellular interactions and is influenced by genetic, environmental, and metabolic factors. Emerging evidence highlights the multiple pathways by which lipids regulate melanogenesis and points to lipid metabolism and signaling as key players in this process. Lipidomics is a high-throughput omics approach that enables detailed characterization of lipid profiles, thus representing a valid tool for evaluating skin lipid functional role in both physiological melanogenesis and pigmentary disorders. The use of lipidomics to gain a deeper comprehension of the role of lipids in skin pigmentation is still an evolving field, but it has allowed the identification of significant lipid dysregulation in several pigmentary pathologies. This review summarizes the current knowledge on the involvement of lipids in skin pigmentation, focusing on lipid profile alterations described in hyper- and hypopigmentary disorders such as post-inflammatory hyperpigmentation, melasma, solar lentigo, and vitiligo. Lipidomic profiling reveals disease-specific alterations supporting the pivotal role of lipid signaling in the physiopathological mechanisms of melanogenesis. These findings provide insights into disease pathogenesis and show promise for the discovery of biomarkers and innovative therapeutic strategies for pigmentary disorders.

Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.

Atopic dermatitis (AD) is a chronic inflammatory disorder presenting a dysregulated immune response and derangement of the epidermal barrier lipids. The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signal axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D-epidermal equivalents. We used tofacitinib, a low-molecular-mass JAK inhibitor, to screen for the JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4, and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase, and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitate and caused a depletion of triglycerides. This depletion was associated with altered PC profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very long chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by halted homeostasis of FA metabolism.

Glucocorticoids (GCs) are commonly used in the treatment of inflammatory skin diseases, although the balance between therapeutic benefits and side effects is still crucial in clinical practice. One of the major and well-known adverse effects of topical GCs is cutaneous atrophy, which seems to be related to the activation of the glucorticoid receptor (GR) genomic pathway. Dissociating anti-inflammatory activity from atrophogenicity represents an important goal to achieve, in order to avoid side effects on keratinocytes and fibroblasts, known target cells of GC action. To this end, we evaluated the biological activity and safety profile of two novel chemical compounds, DE.303 and KL.202, developed as non-transcriptionally acting GR ligands. In primary keratinocytes, both compounds demonstrated anti-inflammatory properties inhibiting NF-κB activity, downregulating inflammatory cytokine release and interfering with pivotal signaling pathways involved in the inflammatory process. Of note, these beneficial actions were not associated with GC-related atrophic effects: treatments of primary keratinocytes and fibroblasts with DE.303 and KL.202 did not induce, contrarily to dexamethasone—a known potent GC—alterations in extracellular matrix components and lipid synthesis, thus confirming their safety profile. These data provide the basis for evaluating these compounds as effective alternatives to the currently used GCs in managing inflammatory skin diseases.