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

Table 1 Multidimensional regulatory landscape of X-inactive specific transcript in spinal cord injury: From mitochondrial metabolism to epigenetic and immune control

Regulatory dimension	Key molecular partners/targets	Core mechanistic action	Functional impact and SCI outcome	Ref.
Epigenetic and chromatin	SAF-A/HNRNPU, PRC1/2, MED14	XIST coating and chromatin anchoring; recruitment of polycomb complexes; suppression of specific enhancers	Maintains XCI integrity and lineage stability in stem cells	Kolpa et al[14], 2016; Bousard et al[15], 2019; Richart et al[16], 2022
Post-transcriptional and metabolic (core axis)	IGF2BP2, CPT1A, NDUFA2	XIST recruits IGF2BP2 (m6A reader) to stabilize CPT1A and NDUFA2 mRNAs; markedly enhances FAO and OXPHOS	Promotes neuronal differentiation of NSCs; increases ATP production and OCR; improves locomotor recovery and reduces neuroinflammation	Zeng et al[1], 2025; Huang et al[4], 2022; Wang et al[11], 2021; Weng et al[17], 2022
Immune-metabolic and ceRNA	miR-124-3p, IRF1	XIST acts as a ceRNA sponge for miR-124-3p, modulating the Irf1 pathway and microglial polarization	Regulates M1/M2 macrophage balance; exerts context-dependent effects on the inflammatory microenvironment	Yang et al[18], 2023
Systemic and intercellular	miR-539-3p, ADAMTS5; MSC-derived exosomes	XIST modulates hepatic mitochondrial injury via Adamts5 axis; XIST-containing EVs facilitate stem-immune crosstalk	Sustains cross-organ energy homeostasis; drives pro-regenerative M2 phenotype through exosomal shuttling of regulatory RNAs	Wu et al[2], 2023; Karpenko[19], 2025; Phinney et al[20], 2015; Arabpour et al[21], 2021

SCI: Spinal cord injury; SAF-A: Scaffold attachment factor A; HNRNPU: Heterogeneous nuclear ribonucleoprotein U; PRC1: Polycom repressive complex 1; PRC2: Polycom repressive complex 2; MED14: Mediator complex subunit 14; XIST: X-inactive specific transcript; XCI: X-chromosome inactivation; IGF2BP2: Insulin-like growth factor 2 mRNA-binding protein 2; CPT1A: Carnitine palmitoyl transferase 1A; NDUFA2: NADH ubiquinone oxidoreductase subunit A2; m⁶A: N6-methyladenosine; FAO: Fatty acid oxidation; OXPHOS: Oxidative phosphorylation; NSCs: Neural stem cells; ATP: Adenosine triphosphate; OCR: Oxygen consumption rate; IRF1: Interferon regulatory factor 1; ceRNA: Competing endogenous RNA; ADAMTS5: A disintegrin and metalloproteinase with thrombospondin motifs 5; MSCs: Mesenchymal stromal/stem cells; EVs: Extracellular vesicles; M1: Classically activated (pro-inflammatory) macrophage phenotype; M2: Alternatively activated (anti-inflammatory/pro-regenerative) macrophage phenotype.