Maintenance of skin homeostasis requires precise coordination of epigenetic regulation, metabolic pathways, and immune signaling. This thesis investigates two critical regulatory mechanisms governing epidermal function and malignant transformation. First, we demonstrate that histone lysine-specific demethylase 1 (LSD1/KDM1A) functions as a critical epigenetic repressor of retinoid responses in skin. While epidermal Lsd1 is essential for embryonic development, its deletion or pharmacological inhibition in adult epidermis activates retinoid signaling and dendritic cell (DC)-T cell infiltration. Mechanistically, LSD1 directly binds retinoid metabolism and immune chemokine loci in keratinocytes, with LSD1 loss increasing H3K4me2 at these sites. Using single-cell spatial profiling, we reveal that LSD1 deficiency triggers a sequential activation of retinoid signaling in specific keratinocyte subsets, followed by DC recruitment and CD4+ T cell infiltration. We also uncover retinoid-dependent and independent immune responses mediated by LSD1 inhibition (LSD1i). Importantly, topical LSD1i restricts skin tumor growth in multiple cutaneous squamous cell carcinoma (cSCC) models by enhancing retinoid-immune crosstalk. We then investigate ferroptosis, an iron-dependent form of cell death, as a novel mechanism controlling epidermal cornification. Inhibition of glutathione peroxidase 4 (GPX4) in primary human keratinocytes induces transcriptional and metabolic reprogramming toward differentiation, characterized by enrichment of cornified layer genes and barrier-associated ceramides. Ferroptosis induction activates endoplasmic reticulum (ER) stress signaling and causes ER membrane disruption through lipid peroxide accumulation. Furthermore, epidermal-specific GPX4 knockout in mice display upregulated cornification genes alongside an inflammatory signature associated with tumor immunosurveillance. This work illuminates promising therapeutic avenues at the intersection of epigenetics, metabolism, and differentiation in the epidermis. Topical formulations targeting LSD1 or ferroptosis modulators may rewire the local tissue environment while minimizing systemic effects, addressing fundamental aberrations in keratinocyte malignancies and other skin diseases.