Apoptosis refers to the programmed cell death that influences various biological processes. During early development, apoptosis facilitates the removal of excess cells to ensure normal development, such as the gradual disappearance of the tadpole tail and the development of human fingers from a duck-like webbed foot [1]. After maturation, apoptosis remains an important part of metabolism and is responsible for the removal of damaged and dysfunctional cells or organelles. Thus, the cells in an organism are in a state of dynamic equilibrium that maintains homeostasis and normal function.

The regulation of apoptosis primarily involves the mitochondrial and death receptor pathways; however, new evidence suggests the involvement of the endoplasmic reticulum (ER) in regulating apoptosis [2]. Exposure to external stimuli can trigger endoplasmic reticulum stress (ERS) potentially caused by the accumulation of unfolded or misfolded proteins in the ER lumen [3]. ERS-induced apoptosis is primarily mediated by four major pathways, namely PERK, IRE1α [4], ATF6, and Ca²⁺, which involve oxidative stress, the activation of AKT and JNK, and the direct activation of caspase-12 [5], ultimately inducing apoptosis.

The hair follicle is a unique mammalian skin structure that plays an indispensable role in skin function and regeneration as one of the important skin appendages. The hair follicle is a microscopic organ with an extremely high capacity for self-renewal and cycling through multiple hair cycles. The hair anatomy comprises, from top to bottom, the infundibulum, isthmus, bulge region, and hair bulb, and if described simply from the inside–out, the hair shaft, inner root sheath, outer root sheath, and connective tissue sheath are included in the dermal sheath (DS) [6].

Hair loss is prevalent worldwide, with chemotherapy-induced alopecia (CIA) being the most common. Although the mechanisms underlying hair loss are not yet entirely understood, apoptosis has been implicated in the pathogenesis of hair loss, particularly in CIA. However, the association between apoptosis and other forms of hair loss, such as alopecia areata (AA), lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and androgenetic alopecia (AGA), remains unclear.

Alopecia is classified into either cicatricial or non-cicatricial. Cicatricial alopecia includes AGA, chemotherapy-induced alopecia areata, and telogen effluvium, while non-cicatricial alopecia includes lichen planopiloaris, frontal fibrosing alopecia, and lupus erythematosus ^[7][106]. Both classes are closely associated with apoptosis of hair follicle cells, most of which correlate with apoptosis of HFSCs. However, in some specific cases of hair loss, multiple factors are involved, such as genetics and the hair follicle microenvironment ^{[8][9][10][11][12]}[107,108,109,110,111].

Androgenetic alopecia (AGA), the most common type of alopecia, is a heritable disease characterized by androgen dependence and a combination of factors in which hair follicles are progressively miniaturized by androgen, leading to hair reduction and thinning, which can occur in males and females ^[12][13][111,112]. Deng ^[14][113] has previously shown that the androgen receptor (AR) in DP cells mediated the paracrine secretion of TGF-β signaling and induced apoptosis of microvascular endothelial cells, thus making it difficult for hair follicles to enter the anagen phase. Xie et al. ^[15][114] showed that androgenetic alopecia-induced shrinkage or loss of the hair shaft caused mechanical compression, while the activation of Piezo1 channels triggered Ca²⁺ inward flow, thereby increasing TNF-α sensitivity and inducing long-term apoptosis in HFSCs.

P53 expression is significantly increased in the hair follicles of the frontal baldness area in patients with AGA, whereas the expressions of the DNA repair marker proteins APE1, PCNA, and PARP-1 were significantly reduced. This suggests that the DNA repair capacity during AGA is not sufficient to counteract the effects of apoptosis ^[16][115]. Conventional treatments for AGA include minoxidil and finasteride. Minoxidil restores hair growth mainly by promoting the microvascular concentration of hair follicles to increase the concentration of growth factors. Finasteride is an inhibitor of 5α-reductase, a key enzyme in the conversion of androgens in vivo, and reduces the conversion of androgenic testosterone to its active form, dihydrotestosterone ^[17][116]. Treatment with natural product extracts or monomers has also been used, such as proanthocyanidins, which inhibit hair epithelial cell apoptosis and thus promote hair growth ^[18][117]. Ginsenoside F2 reduces hair cells apoptosis by modulating TGF-β2 in DHT-induced AGA mice and HaCaT cell models ^[19][118]. Baicalin and linoleic acid reduce hair cell apoptosis by regulating IGF-1 ^[20][21][119,120], while forsythiaside-A, which inhibits hair cell apoptosis by decreasing the expression of caspases-9 and -3 and TGF-β2, delays the entry into the catagen phase ^[22][121].

Alopecia areata (AA) is characterized by common non-scarring alopecia due to autoimmune disorders. Collapse of the immune privilege (IP) of the hair follicle bulb is an important driver of baldness, manifested by lymphocyte infiltration around the hair follicle during the anagen phase ^[23][122]. In immune therapy, drugs such as diphencyprone are used to reduce the aggregation of immune cells around the hair follicles ^[24][123]. By acting as allergens, diphencyprone induces a localized immune response in small areas of the scalp, away from the follicular region. Local subcutaneous injections of steroids are also used in treatment, along with emerging therapies like Janus kinase (JAK) inhibitors that directly inhibit downstream effectors of the immune response ^[25][124]. Additionally, the use of diphencyprone slightly increased the expression of apoptosis inhibitors p16 and survivin in AA patients ^[26][125], and Bcl-2 expression was significantly increased in recovered AA patients’ scalps ^[27][126].

However, there is also a strong genetic association with the development of AA, with significant alterations in the apoptosis/autophagy pathway ^[28][127]. In a case–control analysis, FAS and FASLG gene polymorphisms affected the risk of developing AA; that is, mutations in FAS and FASLG may be a cause of AA ^[29][128]. FAS and FASL-deficient mice are resistant to the development of AA, and AA mice showed more FASL-positive cells than control mice, possibly due to increased FASL gene expression during AA, which caused apoptosis of hair follicle cells ^[30][129].

Chemotherapy-induced alopecia (CIA) is a common adverse effect in patients receiving chemotherapy and manifests as patchy or diffuse anagen alopecia that may progress to complete hair loss within 2–3 months ^[31][130]. There are two forms of damage attributed to CIA: One is the dystrophic anagen phase, in which hairs are stimulated by low doses of chemotherapeutic drugs, manifesting in an outgrowth of the hair shaft and damage to the structure of the hair follicle, which returns to the second cycle, during which hair loss is rare. The other is the dystrophic catagen phase, which refers to the destruction of the hair follicle structure after receiving high doses of chemotherapeutic drugs, characterized by the fragmentation of melanocytes, rapid and massive hair loss, and a rapid subsequent growth cycle within a short period of time ^[32][131].

A common clinical treatment option is scalp cooling to reduce drug damage to hair follicles by reducing the uptake and metabolism of local chemotherapeutic drugs. The active metabolite of CYP, 4-hydroperoxycyclophosphamide 4-HC, causes DNA damage and apoptosis, while PPAR-γ agonist NAGED pretreatment prevented 4-HC-induced apoptosis in human eHFSCs ^[33][132]. Some herbal extracts also have good therapeutic effects on CIA. Ginseng is commonly applied in the treatment of hair loss; for example, Korean red ginseng extract (KRGE) can prevent 4-HC-induced follicular anagen inhibition and premature catagen by reducing P53 and Bax/Bcl2 expression. KRGE also alleviates 4-HC-induced proliferation inhibition and apoptosis in matrix keratinocyte cells ^[34][133]. Monomeric compounds from Chinese herbal medicine also have good prospects for development, such as the decursin in Angelica, which can reduce the expression of PI3K/AKT signaling and MAPK signaling pathways in TNF-α-stimulated keratinocytes. Decursin has also been shown to reduce the expression of apoptosis-related factors and caspase family, while increasing the expression of epidermal growth factor, with certain therapeutic effects against CIA ^[35][134].

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary lymphocytic cicatricial hair loss disorders. Similar to AA, hair follicles attacked by CD8+ cells due to the loss of IP at the bundle site undergo apoptosis and pathological epithelial-to-mesenchymal transition (EMT) of stem cells, and eventually loss of the regenerative capacity of the hair follicles ^[36][135]. HFSCs within the bulge are depleted, which is reflected in the tissue examination of the scalp of patients with LPP, where HFSCs showed an increase in apoptosis ^[37][136]. In contrast, FFA is more oriented toward pathological EMT and hair fibrosis ^[38][137].

Therefore, the most direct route to treat LPP and FFA is to inhibit IP collapse and reduce HFSC apoptosis with drugs such as tacrolimus that inhibits IP collapse in the bulb in vitro ^[39][138] and has undergone clinical trials ^[40][139]. In addition, agonists of the PPAR-γ pathway can partially reverse EMT at the bulb and are effective in isolated LPP hair follicles ^[41][140] and protect K15+ eHFSCs in the bulge region of LPP hair follicles from apoptotic injury, while reducing the number of CD8+ cells and MHCII+ cells among them ^[42][141].

Currently, various pharmaceutical interventions are being investigated to treat these diseases. Drugs that specifically target and regulate apoptosis can be classified into natural remedies and extracts, chemically synthesized, or biologically prepared (Table 1).