The diverse chemical constituents of tobacco are implicated in the pathogenesis of multiple inflammatory dermatoses (47), encompassing AGA (48): ① In humans, nicotine, the primary alkaloid present in tobacco, can be incorporated into hair shafts, whether through systemic absorption into the bloodstream or from direct exposure to environmental smoke (49). Scalp capillary vasoconstriction (leading to long-term malnutrition and hypoxia of HFs and impeding the regeneration of healthy hair) is induced by nicotine through impairing acetylcholine-induced endothelium-dependent cutaneous vasodilation (50, 51). ② Exposure to nicotine and other chemical toxins in tobacco can readily cause persistent inflammatory cell infiltration around HFs, damage nuclear deoxyribonucleic acid (DNA) and mitochondrial DNA in HFSCs and induce oxidative stress (52–56), thereby potentially contributing, in part, to HF miniaturization. ③ Guo L. et al. (57) discovered that cigarette smoke exposure decreased the activity of the Wnt/β-catenin signaling pathway, which is closely related to hair growth.

It was found in Yang W. et al.’s research (58) that the incidence of AGA is higher among alcohol consumers than among abstainers: ① Alcohol consumption trended toward positive genetic correlation with total testosterone in males (59). Elevated testosterone is often accompanied by the occurrence of AGA (20). ② Chronic alcohol consumption may downregulate the Wnt/β-catenin pathway (60) and promote bone morphogenetic protein (BMP) synthesis (61). Activation of the BMP pathway induces irreversible outcomes, including quiescence of HFSCs, shortened anagen phase, and follicular miniaturization, by persistently trans mitting pathological signals that halt growth or by antagonizing the Wnt/β-catenin pathway and directly inhibiting the normal hair cycle (62). ③ Among the known members of the prostaglandin (PG) family, both prostaglandin E2 (PGE2) and F2α (PGF2α) possess hair growth-promoting properties and are indispensable substances for maintaining a healthy hair growth cycle (63). The diminished production of PGE2 and PGF2α resulting from chronic alcohol consumption (64) has a potential detrimental effect on the health of HFs. ④ Almost all alcohol (ethanol) in the human body is metabolized in the liver by alcohol dehydrogenase (ADH) to acetaldehyde, which is subsequently metabolized by aldehyde dehydrogenase (ALDH) to acetic acid. Ethanol and acetaldehyde can generate substantial oxygen species (ROS) and pro-inflammatory factors during metabolic processes (65, 66), thus providing a mechanistic basis that could lead to the suppression of hair growth.

Sleep is an essential physiological function that accounts for one-third of human daily activity. Sleep disturbance can adversely affect human health and may induce or exacerbate AGA (67): ① Sleep deprivation directly disrupts the secretion of multiple hormones critically involved in the hair growth circle. Melatonin is predominantly synthesized in the pineal gland in mammals, with its synthesis and secretion confined to the nocturnal period (68). Zhang Y. et al. (69) believed that melatonin-mediated circadian signals exert a crucial regulatory effect on the state of HFSCs. Owing to the fact that it is not only a sleep hormone but also a potent antioxidant and hair growth regulator that directly stimulates the proliferation of keratinocytes (KCs) of HFs and prolongs the hair growth period (70). Sleep deprivation directly results in decreased melatonin secretion, depriving the essential protective and supportive factor of HFs. ② Cortisol is the end product and a crucial functional biomarker of the hypothalamic–pituitary–adrenal (HPA) axis, exhibiting a circadian rhythm with nadir levels observed around midnight (71). Sleep deprivation leads to increased cortisol levels (72), which may initiate or worsen AGA by inhibiting HFSCs function or hastening the transition of HFs into the catagen phase (37). ③ Extended sleep deprivation may disrupt the equilibrium of androgens and estrogens (73), potentially contributing to an environment that favors the aggravation of AGA (74). ④ One potential function of sleep is to mitigate oxidative stress within the central nervous system and peripheral tissues, facilitating the clearance of reactive metabolites (such as ROS) that accumulated during wakefulness (75). Sleep deprivation probably induces apoptosis in HF-associated cells due to oxidative stress resulting from excessive accumulation of ROS (76, 77). ⑤ A prevalent vicious cycle exists between sleep deprivation and psychological stress, wherein sleep deprivation induces psychological stress, which in turn further disrupts sleep architecture (78). Psychological stress impairs the transition of HFs from the telogen to the anagen phase via activation of the sympathetic nervous system/norepinephrine (NE)/cyclic adenosine monophosphate (cAMP) signaling pathway (79), thereby potentially contributing to the exacerbation of AGA.

In recent years, with the advancement of nationwide fitness initiatives, clinical consultations regarding optimal exercise modalities and intensities for patients with AGA have increased annually. Research (80) has shown that aerobic exercise sessions exceeding 60 min can delay the progression of AGA, with the potential mechanisms including: ① The micronutrient concentrations necessary for HF proliferation are elevated through enhanced hemodynamic circulation and elevated blood oxygen saturation (81). Once adequate blood perfusion to HFs is established, the influx of nutrients and micronutrients may be enhanced. These elements can then be more effectively delivered into the follicular microenvironment, thereby potentially promoting HF proliferation under optimal conditions. ② Circulating testosterone concentrations exhibit an inverted-U relationship with exercise duration, whereby testosterone concentrations initially increase to a peak and then decline, ultimately dropping below baseline with prolonged activity (82–84). ③ Appropriate exercise modalities and intensities also can effectively mitigate stress, alleviate symptoms of anxiety and depression, and enhance sleep quality (85), all of which are factors that could potentially slow the progression of AGA.

However, further research indicates that individuals engaging in high-intensity physical exercises such as sprinting, resistance training, and weightlifting exhibit elevated androgen levels beyond normative ranges (86, 87). Arachidonic acid (AA) that is released during anaerobic exercise due to either micro-tears in muscle fibers (can activate phospholipase A2) or localized hypoxia (88) is rapidly metabolized by cyclooxygenase (COX) into prostaglandins (PGs) (89), which may induce or exacerbate AGA.

One type of non-ionizing electromagnetic radiation in the electromagnetic spectrum is UVR, which comes mainly from the sun. The radiation wavelengths emitted by the sun include ultraviolet A (UVA, 320 ~ 400 nm), ultraviolet B (UVB, 280 ~ 320 nm), and ultraviolet C (UVC, <280 nm). Under normal conditions, human skin is typically exposed solely to ultraviolet B radiation (UVBR) and ultraviolet A radiation (UVAR), which can induce various dermatological pathophysiological processes (90): ① The critical regulatory factor for proliferation of HFs in AGA patients is the equilibrium of various PG subtypes within the scalp (91), which is susceptible to disruption by ultraviolet radiation exposure (92). ② UVR goes through the outer skin layer, damaging DNA and possibly affecting the growth of skin cells around hair follicles (93). ③ Prolonged exposure to UVR can induce a spectrum of immunomodulatory effects at both local and systemic levels. For example, UV exposure elevates the expression of pro-inflammatory cytokines such as Interleukin-1 alpha (IL-1α), IL-1β, IL-6, and TNF-α, promotes the generation of ROS, and mediates oxidative damage to cellular membranes, mitochondria, and DNA (94–97). Collectively, these alterations may contribute to the inhibition of HF proliferation. ④ Long-term UVR exposure induces photoaging of the scalp, manifesting as uneven epidermal thinning, dermal collagen degradation, and degeneration of elastic fibers (EFs) (98). Research elucidates that photoaging also exerts a notable impact on HFs (5): UVAR can lead to a reduction in HFSCs, transit-amplifying cells (TA cells), and melanocytes, which results in HF photoaging characterized by follicular miniaturization and an increase in graying. ⑤ The outermost layer of the hair shaft consists of keratin filament structures, which are highly responsive to environmental stimuli and undergo extensive structural alterations when exposed to UVR. Many lipids that may improve hair quality, such as ceramides, are observed in lower concentrations in UV-exposed hair (99), which may adversely affect hair health and could thereby contribute to hair loss.

The Wnt/β-catenin pathway, which plays a key role in embryonic development and adult tissue homeostasis, is implicated in the pathogenesis of numerous diseases, including AGA, bone disorders, neurodegenerative diseases, and tumors, when dysregulated (109). During the transduction process of the Wnt/β-catenin pathway, Wnt proteins are combined with Frizzled receptors and low-density lipoprotein receptor-related proteins (LRP) co-receptors, resulting in the inactivation of glycogen synthase kinase-3 beta (GSK-3β, a kinase that initiates its ubiquitination and proteasomal degradation through the phosphorylation of β-catenin) of the degradation complex composed predominantly of axis inhibitor (Axin), casein kinase 1 alpha (CK1α), adenomatous polyposis coli (APC), and GSK-3β (110). Therefore, the inactivation of GSK-3β stabilizes cytoplasmic β-catenin. Alternatively, activated disheveled (Dvl) combines with Axin to inhibit GSK-3β activity via phosphorylation, allowing cytosolic β-catenin to evade degradation (111). Stable β-catenin activates a transcriptional cascade of genes that promote HF proliferation and hair growth when it binds to T-cell factor (TCF)/Lymphoid Enhancer Factor (LEF) transcription factors in the nucleus (109) (Figure 2).

PGs, lipid compounds derived from AA metabolism, are widely distributed in tissues and bodily fluids and play roles in numerous physiological processes and inflammatory responses, including cell proliferation, differentiation, and apoptosis (112). PGD2, a signaling molecule derived from AA via COX and prostaglandin D synthase (PGDS) (89), binds to the G protein-coupled receptor 44 (GPR44), resulting in potent suppression of the Wnt/β-catenin pathway and antagonism of pro-hair growth mediators such as PGE2 and PGF2α (91), with a potential consequence being the impairment of HF proliferation.

The testosterone levels, which are converted to DHT with increased AR affinity under the action of 5α-R, may be indirectly elevated due to oxidative stress induced by PGD2 (113). The DHT-AR complexes translocate into the nucleus and competitively bind to TCF/LEF transcription factors, thereby preventing β-catenin from initiating the transcription of genes responsible for hair growth. This process also can inhibit proliferation of HFs by activating the BMP/Smad pathway, which leads to: ① upregulation of ligands like bone morphogenetic protein 4 (BMP4), which activates CXXC type zinc finger protein 5 (CXXC5) to inhibit Dvl; ② insufficient proliferation of HFSCs, triggering follicular miniaturization; and ③ elevated expression of hair growth suppressors such as TNF-α, dickkopf-related protein 1 (DKK-1), and IL-6, ultimately leading to the inhibition of HF proliferation (114–117) (Figure 2).

One of the fundamental requirements of life is redox homeostasis, which permeates the entire process of metabolism throughout the lifespan (118). Oxidative stress refers to the disruption of the redox homeostasis between pro-oxidants and antioxidants. Oxidative stress refers to the disruption of the oxidant-antioxidant balance (118). Once this balance is broken, the dermal papilla cells (DPCs) that regulate the formation, proliferation, and cyclicity of HFs will show obvious oxidative stress characteristics, such as mitochondrial dysfunction, cell apoptosis, and perifollicular inflammation, which is associated with HF miniaturization, a process that can culminate in hair loss (26, 119). Furthermore, the activation of the TGF-β1/Smad pathway by ROS leads to the upregulation of critical apoptotic factors for hair growth, like TGF-β1 and transforming growth factor beta 2 (TGF-β2), thereby triggering senescence and damage of DPCs and ultimately contributing to AGA (120–122). Numerous studies support the interdependence of oxidative stress and inflammation (123, 124): ① Inflammatory cells in the scalp can release substantial amounts of ROS, which exacerbate oxidative damage around the microenvironment of HFs; ② ROS also can exacerbate inflammatory responses, inducing excessive secretion of hair growth inhibitory factors such as IL-1, IL-6, TNF-α, and DKK-1. This bidirectional relationship may induce or exacerbate AGA due to the persistent inflammatory milieu surrounding HFs.

Polak-Witka K. et al. (125) based on metagenomics confirmed that humans’ HFs constitute a complex microecosystem that is inhabited by diverse microbial communities, predominantly hosting symbiotic microbiota such as Malassezia, Cutibacterium, Staphylococcus, etc. Research indicates that approximately 50% of AGA patients’ skin biopsies exhibit a significant infiltration of mononuclear cells (MNCs) and lymphocytes (Lymphs) within the upper third of HFs hosting numerous microorganisms (125), as shown in Figure 3. The excessive proliferation of Malassezia, a key contributor to skin homeostasis, triggers a cascade of events: ① it stimulates KCs to secrete cytokines (such as TNF-α, IL-1β, and IL-6), thereby elevating peribulbar cytokine levels and exacerbating follicular inflammation (30); ② it directly compromises the integrity of HFs via its proteolytic enzymatic activity (30); ③ it generates a substantial amount of ROS that contributes to oxidative stress (126).

The study by Ho BS et al. reported a higher detection rate of Cutibacterium acnes in miniaturization of HFs of AGA patients (43.3%) compared to healthy follicles (7.79%) (127). Cutibacterium acnes possesses a genome that encodes multiple enzymes required for a complete porphyrin metabolic pathway. Porphyrin, the metabolic end product, incites localized follicular inflammation by inducing oxidative stress and promoting the secretion of multiple pro-inflammatory cytokines (128). The clinical presentation of AGA may represent the integrated outcome of a synergistic interplay among multiple pathological mechanisms, including microecological dysbiosis, oxidative stress, and inflammatory responses.