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Theranostics 2024; 14(8):3339-3357. doi:10.7150/thno.93764 This issue Cite

Research Paper

Energy competition remodels the metabolic glucose landscape of psoriatic epidermal cells

Weiwei Liu¹, Jingwei Jiang¹, Zeming Li¹, Yang Xiao¹, Siyi Zhou¹, Dehuan Wang¹, Yi Zou¹, Tiantian Liu¹, Ke Li², Huan Liang², Nian'ou Wang², Xiao Xiang¹, Qiaoli Xie¹, Rixing Zhan^3✉, Jinwei Zhang^1,4✉, Xun Zhou^5✉, Li Yang¹, Cheng-Ming Chuong⁶, Mingxing Lei^1✉

1. Key Laboratory of Biorheological Science and Technology of Ministry of Education & 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
2. Shenzhen Accompany Technology Cooperation, ltd, Shenzhen 518000, China.
3. State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
4. Department of Dermatology, Chongqing General Hospital, Chongqing 401147, China.
5. Department of Dermatology and Cosmetology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China.
6. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

✉ Corresponding authors: Mingxing Lei, E-mail: mingxingedu.cn, Key Laboratory of Biorheological Science and Technology of Ministry of Education & 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. Xun Zhou, E-mail: zhouxun123com, Department of Dermatology and Cosmetology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China. Rixing Zhan, E-mail: zhanrixingcom, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China. Jinwei Zhang, E-mail: skinzjwcom, Department of Dermatology, Chongqing General Hospital, Chongqing 401147, China. More

Abstract

Rationale: Skin cells actively metabolize nutrients to ensure cell proliferation and differentiation. Psoriasis is an immune-disorder-related skin disease with hyperproliferation in epidermal keratinocytes and is increasingly recognized to be associated with metabolic disturbance. However, the metabolic adaptations and underlying mechanisms of epidermal hyperproliferation in psoriatic skin remain largely unknown. Here, we explored the role of metabolic competition in epidermal cell proliferation and differentiation in psoriatic skin.

Methods: Bulk- and single-cell RNA-sequencing, spatial transcriptomics, and glucose uptake experiments were used to analyze the metabolic differences in epidermal cells in psoriasis. Functional validation in vivo and in vitro was done using imiquimod-like mouse models and inflammatory organoid models.

Results: We observed the highly proliferative basal cells in psoriasis act as the winners of the metabolic competition to uptake glucose from suprabasal cells. Using single-cell metabolic analysis, we found that the "winner cells" promote OXPHOS pathway upregulation by COX7B and lead to increased ROS through glucose metabolism, thereby promoting the hyperproliferation of basal cells in psoriasis. Also, to prevent toxic damage from ROS, basal cells activate the glutathione metabolic pathway to increase their antioxidant capacity to assist in psoriasis progression. We further found that COX7B promotes psoriasis development by modulating the activity of the PPAR signaling pathway by bulk RNA-seq analysis. We also observed glucose starvation and high expression of SLC7A11 that causes suprabasal cell disulfide stress and affects the actin cytoskeleton, leading to immature differentiation of suprabasal cells in psoriatic skin.

Conclusion: Our study demonstrates the essential role of cellular metabolic competition for skin tissue homeostasis.

Keywords: OXPHOS, Glucose metabolism, Cell competition, Disulfidptosis

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