Effect of HMGB1 on gp100 Expression and Ferroptosis in Melanocytes and Inflammatory Cascades in Vitiligo

doi:10.3870/j.issn.1672-8009.2026.01.003

Abstract

Abstract: Objective To explore the effect of high mobility group box 1(HMGB1)on pathogenesis of vitiligo through inhibition of glycoprotein 100(gp100) and Nrf-2/HO-1/GPX4 expression,promotion of ferroptosis,and amplification of the inflammatory cascade. Methods A total of 24 C57BL/6 male mice aged 5-6 weeks were randomly divided into 4 groups,with 6 mice in each group:control group,model group,model +HMGB1 treatment group and model +gp100 degrading peptide treatment group.A mouse model of hydroquinone-induced vitiligo was established.The expression levels of HMGB1,gp100,the ferroptosis-related factors(GPX4,SLC7A11)and the endoplasmic reticulum stress-related factors(PERK,p-PERK,ATF6,GRP78,Nrf-2,HO-1)were detected by Western blotting.ELISA was used to measure the levels of TNF-α,IL-6 and MDA.DHE fluorescent probe was used to determine the ROS levels in mice skin tissues.Hematoxylin-eosin(HE)staining and histopathological analysis were performed in mice skin tissues. Results Compared with those in the control group,the score of depigmentation area,the levels of ROS,TNF-α,IL-6,MDA,and the expression levels of HMGB1,SLC7A11,p-PERK,ATF6 and GRP78 in the model group were increased(all P<0.01),whereas the expression levels of gp100 and GPX4 were decreased(P<0.01).The epidermal cells in the model group were disorderly arranged.In the HMGB1 treatment group,the expression levels of Nrf-2,HO-1 and gp100 were decreased(P<0.05),whereas the expression levels of p-PERK,ATF6 and GRP78 were increased(P<0.05).The levels of ROS,MDA and the expression level of SLC7A11 were increased in the gp100 degrading peptide treatment group(P<0.05),and the epidermal cells were more loosely arranged,with a large number of melanocytes undergoing apoptosis. Conclusion HMGB1 may be involved in inhibiting gp100 expression in melanocytes by mediating endoplasmic reticulum stress and inflammatory cascades,and down-regulating Nrf-2/HO-1/GPX4 to promote ferroptosis in melanocytes.

Key words: vitiligo, melanocyte, HMGB1, gp100, endoplasmic reticulum stress, ferroptosis

CLC Number:

R751

GENG Yingying, SUN Zhongbin, HUANG Pengfei, WANG Yunxin, CUI Tingting. Effect of HMGB1 on gp100 Expression and Ferroptosis in Melanocytes and Inflammatory Cascades in Vitiligo[J]. Journal of Medical Molecular Biology, 2026, 23(1): 19-26.

References

[1] LEWITT T M,KUNDU R V.Vitiligo[J].JAMA Dermatol,2021,157(9):1136.
[2] SHELLY PRANIC,ANIKA PULUMATI,DUBRAVKA V-UKOVIC.Protocol for a systematic review and meta-analysis on Janus kinase inhibitors in the management of vitiligo[J].Syst Rev,2024,13(1):110.
[3] FRISOLI M L,ESSIEN K,HARRIS J E.Vitiligo:mechanisms of pathogenesis and treatment[J].Annu Rev Immunol,2020,38:621-648.
[4] 陈蒙,陈晋广.白癜风的现代医学研究进展[J].中国乡村医药,2023,30(7):71-73.
CHEN M,CHEN J G.Advances in research on vitiligo[J].Chin J Rural Med Pharm,2023,30(7):71-73.
[5] IWANOWSKI T,KOŁKOWSKI K,NOWICKI R J,et al.Etiopathogenesis and emerging methods for treatment of vitiligo[J].Int J Mol Sci,2023,24(11):9749.
[6] 李仁夫,吴一菲.难治性白癜风的治疗及进展[J].皮肤病与性病,2024,46(4):234-241.
LI R F,WU Y F.Treatment and progress of refractory vitiligo[J].Dermatol Venereol,2024,46(4):234-241.
[7] JADEJA S D,MAYATRA J M,VAISHNAV J,et al.A concise review on the role of endoplasmic reticulum stress in the development of autoimmunity in vitiligo pathogenesis[J].Front Immunol,2021,11:624566.
[8] WU X,JIN S,YANG Y,et al.Altered expression of ferroptosis markers and iron metabolism reveals a potential role of ferroptosis in vitiligo[J].Pigment Cell Melanoma Res,2022,35(3):328-341.
[9] LI J,CAO F,YIN H L,et al.Ferroptosis:past,present and future[J].Cell Death Dis,2020,11(2):88.
[10] YANG H,WANG H,ANDERSSON U.Targeting inflammation driven by HMGB1[J].Front Immunol,2020,11:484.
[11] MIDDLETON M R,MCALPINE C,WOODCOCK V K,et al.Tebentafusp,a TCR/anti-CD3 bispecific fusion protein targeting gp100,potently activated antitumor immune responses in patients with metastatic melanoma[J].Clin Cancer Res,2020,26(22):5869-5878.
[12] KLARQUIST J,EBY J M,HENNING S W,et al.Functional cloning of a gp100-reactive T-cell receptor from vitiligo patient skin[J].Pigment Cell Melanoma Res,2016,29(3):379-384.
[13] CHEN X,BAO S,LIU M,et al.Inhibition of HMGB1 improves experimental mice colitis by mediating NETs and macrophage polarization[J].Cytokine,2024,176:156537.
[14] ZHU Y,ZHONG L,PENG J,et al.The therapeutic effects of baicalin on vitiligo mice[J].Biol Pharm Bull,2019,42(9):1450-1455.
[15] TOUNI A A,SHIVDE R S,ECHURI H,et al.Melanocyte-keratinocyte cross-talk in vitiligo[J].Front Med,2023,10:1176781.
[16] BARYGINA V,BECATTI M,LOTTI T,et al.ROS-challenged keratinocytes as a new model for oxidative stress-mediated skin diseases[J].J Cell Biochem,2019,120(1):28-36.
[17] SONG P,ZHANG W,GUO S,et al.Membranal expression of calreticulin induced by unfolded protein response in melanocytes:A mechanism underlying oxidative stress-induced autoimmunity in vitiligo[J].J Invest Dermatol,2024,144(7):1622-1632.e5.
[18] LI W,CAO T,LUO C,et al.Crosstalk between ER stress,NLRP3 inflammasome,and inflammation[J].Appl Microbiol Biotechnol,2020,104(14):6129-6140.
[19] KIM S,JOE Y,SURH Y J,et al.Differential regulation of toll-like receptor-mediated cytokine production by unfolded protein response[J].Oxid Med Cell Longev,2018,2018:9827312.
[20] ZHOU M,LIN F,XU W,et al.Decreased SUMOylation of the retinoblastoma protein in keratinocytes during the pathogenesis of vitiligo[J].Mol Med Rep,2018,18(3):3469-3475.
[21] VIEYRA-GARCIA P A,WOLF P.A deep dive into UV-based phototherapy:Mechanisms of action and emerging molecular targets in inflammation and cancer[J].Pharmacol Ther,2021,222:107784.
[22] XU Z,XU J,SUN S,et al.Mecheliolide elicits ROS-mediated ERS driven immunogenic cell death in hepatocellular carcinoma[J].Redox Biol,2022,54:102351.
[23] MA Y,XU P,XING H,et al.Rutin mitigates fluoride-induced nephrotoxicity by inhibiting ROS-mediated lysosomal membrane permeabilization and the GSDME-HMGB1 axis involved in pyroptosis and inflammation[J].Ecotoxicol Environ Saf,2024,274:116195.
[24] QIAO X,LI W,ZHENG Z,et al.Inhibition of the HM-GB1/RAGE axis protects against cisplatin-induced ototoxicity via suppression of inflammation and oxidative stress[J].Int J Biol Sci,2024,20(2):784-800.
[25] KIM Y H,KWAK M S,LEE B,et al.Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion[J].Autophagy,2021,17(9):2345-2362.
[26] HE F,GU L,CAI N,et al.The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress[J].Inflamm Res,2022,71(10-11):1245-1260.
[27] WU Y,ZHAO Y,YANG H Z,et al.HMGB1 regulates ferroptosis through Nrf2 pathway in mesangial cells in response to high glucose[J].Biosci Rep,2021,41(2):BSR20202924.
[28] YANG R,GAO W,WANG Z,et al.Polyphyllin I induced ferroptosis to suppress the progression of hepatocellular carcinoma through activation of the mitochondrial dysfunction via Nrf2/HO-1/GPX4 axis[J].Phytomedicine,2024,122:155135.
[29] YANG W,WANG Y,ZHANG C,et al.Maresin1 protect against ferroptosis-induced liver injury through ROS inhibition and Nrf2/HO-1/GPX4 activation[J].Front Pharmacol,2022,13:865689.
[30] MARTINEZ-PEREZ D,VIÑAL D,SOLARES I,et al.Gp-100 as a novel therapeutic target in uveal melanoma[J].Cancers,2021,13(23):5968.
[31] CHEN J,LI S,LI C.Mechanisms of melanocyte death in vitiligo[J].Med Res Rev,2021,41(2):1138-1166.