X inactive specific transcript drives mitochondrial metabolic rewiring and neural stem cell fate after spinal cord injury

doi:10.4252/wjsc.116228

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World Journal of Stem Cells

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1948-0210

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Stem Cells. Aug 26, 2026; 18(8): 116228
Published online Aug 26, 2026. doi: 10.4252/wjsc.116228

X inactive specific transcript drives mitochondrial metabolic rewiring and neural stem cell fate after spinal cord injury

Jin-Ke Sun, Zhen Shi, Xiao-Dong Tang, Bo-Kang Lv, Peng-Yu Lu, Yi-Gong Tian, Yan-Wei Fan, Peng Yan

Jin-Ke Sun, Yi-Gong Tian, Yan-Wei Fan, Peng Yan, Third Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China

Zhen Shi, Xiao-Dong Tang, Bo-Kang Lv, Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China

Peng-Yu Lu, First Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China

Co-first authors: Jin-Ke Sun and Zhen Shi.

Author contributions: Sun JK and Shi Z contributed equally to this manuscript and are co-first authors. Sun JK, Tang XD, and Lu PY contributed to the methodology; Sun J contributed to conceptualization and writing - original draft; Shi Z contributed to formal analysis, data curation, and figure preparation; Tang XD and Tian YG contributed to investigation; Lv BK and Tian YG contributed to software; Lv BK contributed to data visualization; Lv BK and Fan YW contributed to validation; Lu PY contributed to resources; Tian YG contributed to data interpretation; Fan YW contributed to supervision; Yan P reviewing, editing, and overall supervision. All authors participated in drafting the manuscript and have read, contributed to, and approved the final version of the manuscript.

AI contribution statement: We would like to respectfully clarify that AI-assisted tools were used only as auxiliary tools for language polishing, grammar correction, readability improvement, and limited linguistic refinement. Such use was intended to improve the clarity and fluency of English expression, particularly because the authors are non-native English writers and need to ensure that the manuscript meets the language standards required for international academic publication. The use of AI tools was reasonable, limited, and necessary for language assistance, and it did not replace the authors’ intellectual contribution. No AI tool participated in the study conception, scientific argumentation, literature judgment, interpretation of results, formulation of conclusions, or preparation of figures/images. The scientific content, academic opinions, reference selection, manuscript structure, and final conclusions were independently developed, checked, and approved by the authors. We confirm that the use of AI-assisted tools did not violate academic ethics or authorship responsibilities.

Supported by Key Scientific Research Projects of Colleges and Universities in Henan Province, No. 26A320038; Henan Province Medical Science and Technology Research Plan Project (Joint Construction), No. LHGJ20250403, No. LHGJ20220566, and No. LHGJ20240365; Key Research and Development Program of Henan Province, No. 231111311000; and Medical Education Research Project in Henan Province, No. WJLX2023079.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Corresponding author: Peng Yan, MD, PhD, Chief Physician, Professor, Third Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, No. 3 Kangfu Qianjie, Erqi District, Zhengzhou 450052, Henan Province, China. summun1980@sina.com

Received: November 6, 2025
Revised: January 16, 2026
Accepted: February 28, 2026
Published online: August 26, 2026
Processing time: 287 Days and 23 Hours

Abstract

Spinal cord injury triggers irreversible functional loss and metabolic collapse, where mitochondrial dysfunction creates a critical bottleneck for regenerative therapies. Zeng et al recently published a study in World Journal of Stem Cells identify the long noncoding RNA X-inactive specific transcript (XIST) as a master regulator of mitochondrial metabolism and neural stem cell fate through the insulin-like growth factor 2 mRNA-binding protein 2/carnitine palmitoyl transferase 1A axis. By stabilizing carnitine palmitoyl transferase 1A mRNA via insulin-like growth factor 2 mRNA-binding protein 2, XIST enhances fatty acid oxidation and oxidative phosphorylation, thereby driving neuronal differentiation while curbing reactive astrogliosis in murine models. Beyond metabolic control, XIST interfaces with chromatin remodeling and inflammatory signaling, although its multifaceted roles are highly context-dependent. Despite therapeutic promise, challenges regarding lineage-specific effects and the need for longitudinal in vivo validation persist. Future strategies integrating spatial transcriptomics and advanced delivery systems are essential to translate XIST-mediated mechanisms into clinical spinal cord injury repair.

Keywords: Carnitine palmitoyltransferase 1A; Insulin like growth factor 2 messenger RNA binding protein 2; Long noncoding RNA; Mitochondrial metabolism; Neural stem cells; Regenerative medicine; Spinal cord injury; X inactive specific transcript

Core Tip: This study highlights the pivotal role of the long noncoding RNA X inactive specific transcript as a metabolic-epigenetic regulator in spinal cord injury. By stabilizing carnitine palmitoyltransferase 1A messenger RNA through insulin like growth factor 2 messenger RNA binding protein 2, it enhances fatty acid oxidation and mitochondrial oxidative phosphorylation, promoting neural stem cell differentiation and functional recovery. The proposed framework integrates mitochondrial metabolism, lineage regulation, and regenerative strategies, providing a conceptual bridge from molecular mechanisms to translational medicine.