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Abstract Alopecia is traditionally classified into scarring and nonscarring subtypes, with etiopathologies ranging from androgen‐mediated to immuno‐inflammatory. Over 50% of men and almost 50% of women will experience some form of hair loss in their lifetime. Given this prevalence and the psychosocial significance of hair, understanding the pathophysiology and comorbidities of different types of hair loss is imperative. Other proinflammatory dermatologic disorders, such as psoriasis, are recognised to have systemic manifestations including an increased risk of cardiovascular (CV) disease, and are now considered CV risk‐enhancing conditions. With increased recognition of the importance of systemic inflammation in promoting atherosclerosis, high prevalence, and improved treatment strategies, there is increased interest in establishing whether a similar association between alopecia and cardiovascular disease (CVD) exists. In this manuscript, we aim to review the current literature regarding CV risk in androgenic alopecia (AGA) and alopecia areata (AA). Additionally, we review the literature for cicatricial alopecias and highlight the need for more research into their potential associations with CV risk. Evidence from the identified AGA publications suggests an association of AGA with CV risk factors including hypertension, dyslipidemia, and insulin resistance, as well as with coronary artery disease. For AA, most of the identified studies found an association between AA and CV risk, though the relationships were not always statistically significant. Research on cicatricial alopecias and CV risk is limited and often contradictory. There is great need for more studies regarding the association between various types of alopecia and the development of CVD, and potential mechanisms. Particularly needed are more studies of cicatricial alopecias and potential associated CV risk. While some literature suggests that patients with alopecia have an increased risk of CVD, the lack of concrete evidence represents a notable gap in our current understanding.

Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.

Vitiligo, an acquired depigmentation disorder, manifests as white macules on the skin and can cause significant psychological stress and stigmatization. Recent advances have shed light on key components that drive disease onset and progression as well as therapeutic approaches. Vitiligo can be triggered by stress to the melanin pigment-producing cells of the skin, the melanocytes. The triggers, which range from sunburn to mechanical trauma and chemical exposures, ultimately cause an autoimmune response that targets melanocytes, driving progressive skin depigmentation. The most significant progress in our understanding of disease etiology has been made on three fronts: (1) identifying cellular responses to stress, including antioxidant pathways and the unfolded protein response (UPR), as key players in disease onset, (2) characterizing immune responses that target melanocytes and drive disease progression, and (3) identifying major susceptibility genes. The current model for vitiligo pathogenesis postulates that oxidative stress causes cellular disruptions, including interruption of protein maturation in the endoplasmic reticulum (ER), leading to the activation of the UPR and expression of UPR-regulated chemokines such as interleukin 6 (IL-6) and IL-8. These chemokines recruit immune components to the skin, causing melanocytes to be targeted for destruction. Oxidative stress can further increase melanocyte targeting by promoting antigen presentation. Two key components of the autoimmune response that promote disease progression are the interferon (IFN)-γ/CXCL10 axis and IL-17-mediated responses. Several genome-wide association studies support a role for these pathways, with the antioxidant gene NRF2, UPR gene XBP1, and numerous immune-related genes including class I and class II major histocompatibility genes associated with a risk for developing vitiligo. Novel approaches to promote repigmentation in vitiligo are being investigated and may yield effective, long-lasting therapies.