Vitamin D is a fat-soluble vitamin primarily synthesized through skin exposure to ultraviolet B irradiation and dietary intake. Its biological effects are not limited to the regulation of calcium and phosphorus metabolism but also involve a variety of physiological functions such as immune modulation, anti-inflammation, and anti-tumor. In recent years, as research deepens, the role of the vitamin D signaling pathway in various diseases has been gradually revealed, and its regulatory mechanisms are complex and diverse. This paper systematically reviews the molecular mechanisms underlying the vitamin D signaling pathway, including the two-step hydroxylation activation process of vitamin D, the regulation of gene transcription mediated by the vitamin D receptor (VDR), the homeostatic regulation involving vitamin D-binding protein and metabolic enzymes such as 1α-hydroxylase and 24-hydroxylase, and interactions with other signaling pathways, including NF-κB, Wnt, and Hedgehog. This study highlights the role of vitamin D in various multi-system diseases such as inflammatory bowel disease, diabetes and its complications, obesity, cardiovascular disease, colorectal cancer, breast cancer, among others. The systematic cognitive framework for understanding the vitamin D signaling pathway was conducted, providing a theoretical basis for precision treatment strategies targeting VDR.

1.张丽华, 庞丽霞, 林涛, 等. 某院风湿免疫科成年患者25-羟维生素D水平现况调查[J]. 药物流行病学杂志, 2016, 25(5): 326-328. [Zhang LH, Pang LX, Lin T, et al. Investigation of 25-hydroxyvitamin D levels in adult patients in rheumatology and immunology department of a hospital[J]. Chinese Journal of Pharmacoepidemiology, 2016, 25(5): 326-328.] DOI: 10.19960/j.cnki.issn1005-0698.2016.05.015.

2.王珏, 边平达, 寿张轩, 等. 高龄女性服用复方钙剂与骨密度和骨代谢标志物的关系[J]. 药物流行病学杂志, 2017, 26(7): 496-498. [Wang J, Bian PD, Shou ZX, et al. Relationship between calcium supplementation and bone mineral density and bone metabolic markers in elderly women[J]. Chinese Journal of Pharmacoepidemiology, 2017, 26(7): 496-498.] DOI: 10.19960/j.cnki.issn1005-0698.2017.07.012.

3.张浩, 刘爽, 皮琦, 等. 维生素D对结核病的治疗与预防研究进展[J]. 药物流行病学杂志, 2022, 31(10): 705-708. [Zhang H, Liu S, Pi Q, et al. Research progress of vitamin D in the treatment and prevention of tuberculosis[J]. Chinese Journal of Pharmacoepidemiology, 2022, 31(10): 705-708.] DOI: 10.19960/j.cnki.issn1005-0698.2022.10.011.

4.Delrue C, Speeckaert MM. Vitamin D and vitamin D-binding protein in health and disease[J]. Int J Mol Sci, 2023, 24(5): 4642. DOI: 10.3390/ijms24054642.

5.Webb AR, Decosta BR, Holick MF. Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation[J]. J Clin Endocrinol Metab, 1989, 68(5): 882-887. DOI: 10.1210/jcem-68-5-882.

6.Hollis BW, Wagner CL. Clinical review: the role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes[J]. J Clin Endocrinol Metab, 2013, 98(12): 4619-4128. DOI: 10.1210/jc.2013-2653.

7.Saponaro F, Saba A, Zucchi R. An update on vitamin D metabolism[J]. Int J Mol Sci, 2020, 21(18): 6573. DOI: 10.3390/ijms21186573.

8.Carlberg C. Vitamin D and its target genes[J]. Nutrients, 2022, 14(7): 1354. DOI: 10.3390/nu14071354.

9.侯宇, 李景辉, 邓超. 维生素D /维生素D受体、自噬与感染[J]. 中南大学学报（医学版）, 2022, 47(6): 780-785. [Hou Y, Li J, Deng C. Vitamin D/vitamin D receptor, autophagy, and infection[J]. Journal of Central South University Medical sciences, 2022, 47(6): 780-785.] DOI: 10.11817/j.issn.1672-7347.2022.210556.

10.Levy RJ, Howard SL, Oshry LJ. Carboxyglutamic acid (Gla) containing proteins of human calcified atherosclerotic plaque solubilized by EDTA. Molecular weight distribution and relationship to osteocalcin[J]. Atherosclerosis, 1986, 59(2): 155-160. DOI: 10.1016/0021-9150(86)90044-4.

11.Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3[J]. FASEB J, 2005, 19(9): 1067-1077. DOI: 10.1096/fj.04-3284com.

12.Dusso AS, Negrea L, Gunawardhana S, et al. On the mechanisms for the selective action of vitamin D analogs[J]. Endocrinology, 1991, 128(4): 1687-1692. DOI: 10.1210/endo-128-4-1687.

13.Harrison SR, Li D, Jeffery LE, et al. Vitamin D, autoimmune disease and rheumatoid arthritis[J]. Calcif Tissue Int, 2020, 106(1): 58-75. DOI: 10.1007/s00223-019-00577-2.

14.Luo W, Hershberger PA, Trump DL, et al. 24-Hydroxylase in cancer: impact on vitamin D-based anticancer therapeutics[J]. J Steroid Biochem Mol Biol, 2013, 136: 252-257. DOI: 10.1016/j.jsbmb.2012.09.031.

15.Ismail MT, Jinge Z, Hector FD, et al. Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: homology modelling, molecular dynamics simulations and identification of key binding requirements[J]. Bioorg Med Chem, 2017, 25(20): 5629-5636. DOI: 10.1016/j.bmc.2017.08.036.

16.乔俊英, 宋丽, 张艳丽, 等. 哮喘小鼠HMGB1/TLR4/NF-κB信号通路及维生素D的作用[J]. 中国当代儿科杂志, 2017, 19(1): 95-103. [Qiao JY, Song L, Zhang YL, et al. HMGB1/TLR4/NF-κB signaling pathway and role of vitamin D in asthmatic mice[J]. Chinese Journal of Contemporary Pediatrics, 2017, 19(1): 95-103.] DOI: 10.7499/j.issn.1008-8830.2017.01.016.

17.Pálmer HG, González-Sancho JM, Espada J, et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling[J]. J Cell Biol, 2001, 154(2): 369-387. DOI: 10.1083/jcb.200102028.

18.Shah S, Islam MN, Dakshanamurthy S, et al. The molecular basis of vitamin D receptor and beta-catenin crossregulation[J]. Mol Cell, 2006, 21(6): 799-809. DOI: 10.1016/j.molcel.2006.01.037.

19.Aguilera O, Peña C, García JM, et al. The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells[J]. Carcinogenesis, 2007, 28(9): 1877-1884. DOI: 10.1093/carcin/bgm094.

20.Bijlsma MF, Spek CA, Zivkovic D, et al. Repression of smoothened by patched-dependent (pro-) vitamin D3 secretion[J]. PLoS Biol, 2006, 4(8): e232. DOI: 10.1371/journal.pbio.0040232.

21.Li CP, Su HQ, He LP. Vitamin D may alleviate pre-eclampsia by modulating the ferroptosis signalling pathway: a hypothesis based on recent literature[J]. J Cell Mol Med, 2023, 27(14): 1923-1927. DOI: 10.1111/jcmm.17754.

22.Xiao JH, Durand B, Chambon P, et al. Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers are the major functional forms regulating retinoid-responsive elements in adult human keratinocytes. Binding of ligands to RAR only is sufficient for RAR-RXR heterodimers to confer ligand-dependent activation of hRAR beta 2/RARE (DR5)[J]. J Biol Chem, 1995, 270(7): 3001-3011. DOI: 10.1074/jbc.270.7.3001.

23.高玲, 袁天, 陈代娣, 等. 维生素D与代谢性炎症的研究进展[J]. 生命科学, 2019, 31(10): 1060-1068. [Gao L, Yuan T, Chen DD, et al. Research progress of vitamin D and metabolic inflammation[J]. Science China (Life Sciences), 2019, 31(10): 1060-1068.] DOI: 10.13376/j.cbls/2019131.

24.Behm C, Blufstein A, Gahn J, et al. 1,25(OH)2D3 differently affects immunomodulatory activities of mesenchymal stem cells depending on the presence of TNF-α, IL-1β and IFN-γ[J]. J Clin Med, 2019, 8(12): 2211. DOI: 10.3390/jcm8122211.

25.Mousa H, Al Saei A, Razali RM, et al. Vitamin D status affects proteomic profile of HDL-associated proteins and inflammatory mediators in dyslipidemia[J]. J Nutr Biochem, 2024, 123: 109472. DOI: 10.1016/j.jnutbio.2023.109472.

26.Vernia F, Valvano M, Longo S, et al. Vitamin D in inflammatory bowel diseases. mechanisms of action and therapeutic implications[J]. Nutrients, 2022, 14(2): 269. DOI: 10.3390/nu14020269.

27.Pittas AG, Kawahara T, Jorde R, et al. Vitamin D and risk for type 2 diabetes in people with prediabetes: a systematic review and Meta-analysis of individual participant data From 3 randomized clinical trials[J]. Ann Intern Med, 2023, 176(3): 355-363. DOI: 10.7326/M22-3018.

28.Athanassiou L, Kostoglou-Athanassiou I, Koutsilieris M, et al. Vitamin D and autoimmune rheumatic diseases[J]. Biomolecules, 2023, 13(4): 709. DOI: 10.3390/biom13040709.

29.Szymczak-Pajor I, Sliwinska A. Analysis of association between vitamin D deficiency and insulin resistance[J]. Nutrients, 2019, 11(4): 794. DOI: 10.3390/nu11040794.

30.Lei M, Liu Z, Guo J. The emerging role of vitamin D and vitamin D receptor in diabetic nephropathy[J]. Biomed Res Int, 2020, 2020: 4137268. DOI: 10.1155/2020/4137268.

31.Ren Z, Li W, Zhao Q, et al. The impact of 1,25-dihydroxy vitamin D3 on the expressions of vascular endothelial growth factor and transforming growth factor-β1 in the retinas of rats with diabetes[J]. Diabetes Res Clin Pract, 2012, 98(3): 474-480. DOI: 10.1016/j.diabres.2012.09.028.

32.Van Quill KR, Dioguardi PK, Tong CT, et al. Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma[J]. Ophthalmology, 2005, 112(6): 1151-1158. DOI: 10.1016/j.ophtha.2004.11.060.

33.Albert DM, Scheef EA, Wang S, et al. Calcitriol is a potent inhibitor of retinal neovascularization[J]. Invest Ophthalmol Vis Sci, 2007, 48(5): 2327-2334. DOI: 10.1167/iovs.06-1210.

34.Szymczak-Pajor I, Miazek K, Selmi A, et al. The action of vitamin D in adipose tissue: is there the link between vitamin D deficiency and adipose tissue-related metabolic disorders?[J]. Int J Mol Sci, 2022, 23(2): 956. DOI: 10.3390/ijms23020956.

35.Kong J, Li YC. Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells[J]. Am J Physiol Endocrinol Metab, 2006, 290(5): E916-E924. DOI: 10.1152/ajpendo.00410.2005.

36.Chang E, Kim Y. Vitamin D decreases adipocyte lipid storage and increases NAD-SIRT1 pathway in 3T3-L1 adipocytes[J]. Nutrition, 2016, 32(6): 702-708. DOI: 10.1016/j.nut.2015.12.032.

37.Sergeev IN. Vitamin D status and vitamin D-dependent apoptosis in obesity[J]. Nutrients, 2020, 12(5): 1392. DOI: 10.3390/nu12051392.

38.Sergeev IN, Song QM. High vitamin D and calcium intakes reduce diet-induced obesity in mice by increasing adipose tissue apoptosis[J]. Mol Nutr Food Res, 2014, 58(6): 1342-1348. DOI: 10.1002/mnfr.201300503.

39.Anderson JL, May HT, Horne BD, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population[J]. Am J Cardiol, 2010, 106(7): 963-968. DOI: 10.1016/j.amjcard.2010.05.027.

40.Wan ZZ, Guo JY, Pan A, et al. Association of serum 25-hydroxyvitamin D concentrations with all-cause and cause-specific mortality among individuals with diabetes[J]. Diabetes Care, 2021, 44(2): 350-357. DOI: 10.2337/dc20-1485.

41.Raslan E, Soliman SSA, Nour ZA, et al. Association of vitamin D deficiency with chronic stable angina: a case control study [J]. High Blood Press Cardiovasc Prev, 2019, 26(1): 77-80. DOI: 10.1007/s40292-018-0295-7.

42.Brøndum-Jacobsen P, Benn M, Jensen GB, et al. 25-hydroxyvitamin D levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and Meta-analyses of 18 and 17 studies[J]. Arterioscler Thromb Vasc Biol, 2012, 32(11): 2794-2802. DOI: 10.1161/ATVBAHA. 112.248039.

43.Driggin E, Madhavan MV, Gupta A. The role of vitamin D in cardiovascular disease and COVID-19[J]. Rev Endocr Metab Disord, 2022,23(2):293-297. DOI: 10.1007/s11154-021-09674-w.

44.Cosentino N, Campodonico J, Milazzo V, et al. Vitamin D and cardiovascular disease: current evidence and future perspectives[J]. Nutrients, 2021, 13(10): 3603. DOI: 10.3390/nu13103603.

45.Yuan W, Pan W, Kong J, et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter[J]. J Biol Chem, 2007, 282(41): 29821-29830. DOI: 10.1074/jbc.M705495200.

46.Li Y C, Kong J, Wei M, et al. 1,25-dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system[J]. J Clin Invest, 2002, 110(2): 229-238. DOI: 10.1172/JCI15219.

47.Chen S, Swier VJ, Boosani CS, et al. Vitamin D deficiency accelerates coronary artery disease progression in swine[J]. Arterioscler Thromb Vasc Biol, 2016, 36(8): 1651-1659. DOI: 10.1161/ATVBAHA.116.307586.

48.Rodriguez AJ, Mousa A, Ebeling PR, et al. Effects of vitamin D supplementation on inflammatory markers in heart failure: a systematic review and Meta-analysis of randomized controlled trials[J]. Sci Rep, 2018, 8(1): 1169. DOI: 10.1038/s41598-018-19708-0.

49.Songyang Y, Song T, Shi Z, et al. Corrigendum to "effect of vitamin D on malignant behavior of non-small cell lung cancer cells". [Gene 768 (2021) 145309][J]. Gene, 2022, 846: 146883. DOI: 10.1016/j.gene.2022.146883.

50.El-Sharkawy A, Malki A. Vitamin D Signaling in inflammation and cancer: molecular mechanisms and therapeutic implications[J]. Molecules, 2020, 25(14): 3219. DOI: 10.3390/molecules25143219.

51.Wu X, Hu W, Lu L, et al. Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment[J]. Acta Pharm Sin B, 2019, 9(2): 203-219. DOI: 10.1016/j.apsb.2018.09.002.

52.Razak S, Afsar T, Almajwal A, et al. Retraction note: growth inhibition and apoptosis in colorectal cancer cells induced by vitamin D-nanoemulsion (NVD): involvement of Wnt/β-catenin and other signal transduction pathways[J]. Cell Biosci, 2024, 14(1): 77. DOI: 10.1186/s13578-024-01262-0.

53.Hu PS, Li T, Lin JF, et al. VDR-SOX2 signaling promotes colorectal cancer stemness and malignancy in an acidic microenvironment[J]. Signal Transduct Target Ther, 2020, 5(1): 183. DOI: 10.1038/s41392-020-00230-7.

54.Beyerle J, Frei E, Stiborova M, et al. Biotransformation of xenobiotics in the human colon and rectum and its association with colorectal cancer[J]. Drug Metab Rev, 2015, 47(2): 199-221. DOI: 10.3109/03602532.2014.996649.

55.De La Puente-Yagüe M, Cuadrado-Cenzual MA, Ciudad-Cabañas MJ, et al. Vitamin D: and its role in breast cancer[J]. Kaohsiung J Med Sci, 2018, 34(8): 423-427. DOI: 10.1016/j.kjms.2018.03.004.

56.张远东, 赵晖, 李康健. 维生素D对前列腺癌的作用机制研究进展[J]. 临床泌尿外科杂志, 2017, 32(4): 319-323. [Zhang YD, Zhao H, Li KJ. Research progress of the mechanism of action of vitamin D in prostate cancer[J]. Journal of Clinical Urology, 2017, 32(4): 319-323.] DOI: 10.13201/j.issn.1001- 1420.2017.04.019.

57.Yiyan S, Yang S, Li D, et al. Vitamin D affects the warburg effect and stemness maintenance of non- small-cell lung cancer cells by regulating the PI3K/AKT/mTOR signaling pathway[J]. Curr Cancer Drug Targets, 2022, 22(1): 86-95. DOI: 10.2174/1568009621666210729100300.

58.González-Sancho JM, Larriba MJ, Muñoz A. Wnt and vitamin D at the crossroads in solid cancer[J]. Cancers (Basel), 2020, 12(11): 3434. DOI: 10.3390/cancers12113434.

59.Martens PJ, Gysemans C, Verstuyf A,et al. Vitamin D's effect on immune function[J]. Nutrients, 2020, 12(5): 1248. DOI: 10.3390/nu12051248.

60.Kraemer AN, Schäfer AL, Sprenger DTL, et al. Impact of dietary vitamin D on immunoregulation and disease pathology in lupus-prone NZB/W F1 mice[J]. Front Immunol, 2022, 13: 933191. DOI: 10.3389/fimmu.2022.933191.

61.Bruce D, Cantorna MT. Intrinsic requirement for the vitamin D receptor in the development of CD8αα-expressing T cells[J]. J Immunol, 2011, 186(5): 2819-2825. DOI: 10.4049/jimmunol.1003444.

62.Dankers W, Colin EM, Van Hamburg JP, et al. Vitamin D in autoimmunity: molecular mechanisms and therapeutic potential[J]. Front Immunol, 2016, 7: 697. DOI: 10.3389/fimmu.2016.00697.

63.Ao T, Kikuta J, Ishii M. The effects of vitamin D on immune system and inflammatory diseases[J]. Biomolecules, 2021, 11(11): 1624. DOI: 10.3390/biom11111624.

64.Vasile M, Corinaldesi C, Antinozzi C, et al. Vitamin D in autoimmune rheumatic diseases: a view inside gender differences[J]. Pharmacol Res, 2017, 117: 228-241. DOI: 10.1016/j.phrs.2016.12.038.

65.Charoenngam N. Vitamin D and rheumatic diseases: a review of clinical evidence[J]. Int J Mol Sci, 2021, 22(19): 10659. DOI: 10.3390/ijms221910659.

66.Ganmaa D, Uyanga B, Zhou X, et al. Vitamin D supplements for prevention of tuberculosis infection and disease[J]. N Engl J Med, 2020, 383(4): 359-368. DOI: 10.1056/NEJMoa1915176.

67.Mily A, Rekha RS, Kamal SM, et al. Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis[J]. BMC Pulm Med, 2013, 13: 23. DOI: 10.1186/1471-2466-13-23.

68.Xue LN, Xu KQ, Zhang W, et al. Associations between vitamin D receptor polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a Meta-analysis[J]. Inflamm Bowel Dis, 2013, 19(1): 54-60. DOI: 10.1002/ibd.22966.

69.Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and Meta-analysis[J]. Lancet, 2014, 383(9912): 146-155. DOI: 10.1016/S0140-6736(13)61647-5.