Highland animals have unique hair growth mechanisms to allow them to adapt to harsh living environments. Compared with other species, their hair cycle growth is affected by more environmental factors. Yaks, as highland animals, have obvious periodic hair growth characteristics in a year; this biological process is regulated by numerous proteins, but the specific molecular regulatory mechanism is still unclear. Here we analyzed the histological characteristics of yak hair follicles (HFs) at each stage and conducted TMT proteomics research. The protein expression network of yak hair at each stage and the mechanism of the yak HF growth cycle were systematically explored, and the candidate proteins Sfrp1 and Ppard were verified. A total of 3176 proteins were quantifiable and 1142 differentially expressed proteins (DEPs) were obtained at five stages of the yak hair cycle. DEPs enriched in complement activation change, tissue development, lipid metabolism, WNT pathway, VEGF pathway, JAK-STAT pathway, and PPAR pathway may promote the growth of yak hair follicles, such as Serpinf1, Ppard, and Stat3. DEPs enriched in complement system, coagulation, cell adhesion, lipid metabolic process, proliferation of epidermal cells, and estrogen pathway may promote the degeneration of yak hair, such as Sfrp1, Eppk1, and Egfr. Using Protein-Protein Interaction (PPI) analysis, we found that core nodes of DEP networks in yak skin are significantly different at three critical time points in hair follicle development, and lipid metabolism proteins are common core DEP nodes during yak HF growth and degeneration. The expression of Sfrp1 and Ppard in yak hair follicles at different periods showed they are related to yak hair cycle control. This study showed that the protein regulatory network of the yak HF growth cycle is complex and dynamically changing and revealed key candidate proteins that may affect yak hair follicle development. These findings provided detailed data for further understanding of the plateau adaptation mechanism of the yak, which is of great significance to make better use of the yak livestock resources and enhance their economic value.

Background: In the cold plateau environment, the yak’s coat exhibits significant adaptive regulation to cope with adverse conditions. This adaptation is fundamentally governed by the cycle of hair follicles (HFs), a complex process involving numerous molecular signals. However, the key regulators and underlying pathways remain poorly understood. Methods: Proteomic and non-targeted metabolomic analyses were employed to systematically investigate changes in proteins and metabolites during the cycle of yak hair follicles. We further validated the expression dynamics of PPARβ/δ and its related molecules, as well as the specific biological role of PPARβ/δ in regulating lipid metabolism and influencing the proliferation and apoptosis of yak dermal papilla cells (DPCs). Results: Proteomic results indicated that lipid-related proteins were among the most significantly altered, second only to hair structural proteins. The PPAR signaling pathway, which regulates lipid metabolism, may also play an important role in the cycle of yak HF. Non-targeted metabolomics revealed that Fatty Acyls were the most significantly altered metabolites during the transitions into anagen and catagen. Notably, unsaturated long-chain fatty acids (PPARβ/δ agonists) were consistently up-regulated in anagen and down-regulated in catagen, whereas saturated long-chain fatty acids (lacking PPARβ/δ agonist activity) did not exhibit a similar trend. PPARβ/δ shows significant expression changes in the dermal papilla (DP) and hair matrix (HM) during the cycle of yak HFs. Specifically, PPARβ/δ expression in the DP underwent progressive downregulation during the transition from anagen to catagen and subsequently to telogen, becoming nearly undetectable in the telogen DP. Cellular experiments confirmed that PPARβ/δ activation significantly reduced intracellular lipid content in yak DPCs and was accompanied by increased proliferation. Conversely, PPARβ/δ inhibition led to intracellular lipid accumulation and decreased proliferation. Conclusions: These findings suggest that PPARβ/δ may regulate the yak HF cycle by modulating lipid metabolism in DP. The level of intrinsic lipid metabolism within HFs may be a key factor influencing yak HF growth.

Yaks (Bos grunniens) are large mammals endemic to the Qinghai–Tibet Plateau. Efficient lung development is crucial for their adaptation to high-altitude hypoxia. As progenitor cells of the alveoli, type II alveolar epithelial (AT2) cells warrant further investigation into their physiological functions; however, relevant studies remain limited. In this study, primary AT2 cells were isolated from the lungs of yaks. Concurrently, lung tissues were collected from yaks at distinct developmental stages to investigate the role of the EGF/EGFR axis in regulating AT2 cell proliferation and apoptosis, as well as its essential contribution to yak lung development. Here, we demonstrate that the EGF/EGFR axis plays a beneficial role in yak alveolar development. Exogenous EGF supplementation or EGFR activation upregulated the downstream factors AKT and STAT3, enhanced AT2 cell proliferation, and reduced apoptosis. In contrast, EGFR inhibition promoted AT2 cell apoptosis and suppressed proliferation. Cell cycle analysis revealed that both exogenous EGF and EGFR activation increased the proportion of AT2 cells in the S and G2 phases, whereas EGFR inhibition caused cell cycle arrest at the G0/G1 phase. Moreover, the expression of cell cycle regulators cyclin D1, CDK4, and CDK6 was upregulated, while p16 and p21 expression was downregulated. Further comparative analyses indicated that the EGF/EGFR axis positively contributes to alveolar development in juvenile yaks. Collectively, these findings confirm that in plateau environments, activation of the EGF/EGFR axis promotes AT2 cell proliferation and inhibits apoptosis, thereby facilitating alveolar development in juvenile yaks. A key limitation is the lack of parallel comparisons with low-altitude cattle and other plateau-endemic species (e.g., Tibetan sheep), which precludes definitive assessment of the specificity of the EGFR/EGF axis in yak AT2 cell proliferation and lung development.