X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disease caused by pathogenic variants in the ATP binding cassette (ABC) subfamily D member 1 (ABCD1) gene, which is located on the X chromosome (Xq28) and encodes the peroxisomal transporter of CoA-activated saturated very long–chain FAs (VLCFAs; ≥22 C atoms). Pathogenic variants in ABCD1 lead to impaired import of VLCFAs into peroxisomes, resulting in reduced peroxisomal VLCFA β-oxidation and their accumulation in plasma and tissue, including adrenal glands, spinal cord, and brain (reviewed in [16]). In childhood, males with X-ALD often develop progressive damage of the adrenal cortex and wide-spread detoriation of the myelin sheath surrounding the axons in cerebral white matter, so called demyelination. In adulthood, both males and females develop a slowly progressive myeloneuropathy [17]. There are several theories on how the accumulation of VLCFAs leads to cellular and tissular damage. These mechanisms range from VLCFAs disrupting membrane phospholipid function and stability, to enhancing the production of reactive oxygen species and exerting direct cytotoxic effects (reviewed in [18]).

Given that cellular accumulation of VLCFAs is the primary pathological hallmark of X-ALD, therapeutic strategies focused on normalizing VLCFA levels have been regarded as central to treatment approaches. However, emerging evidence indicates that VLCFA quality, rather than or in addition to quantity, underpins their harmful impact in X-ALD. By using human X-ALD fibroblasts and a zebrafish Abcd1 mutant model, metabolic rerouting of saturated to monounsaturated VLCFAs by SCD1 was found to attenuate lipid toxicity (Fig. 1) [19]. Specifically, the authors demonstrated that enhancing SCD1 expression and activity using an agonist for liver X receptor (LXR), a nuclear receptor which senses cholesterol and regulates the expression of lipid metabolism genes including Scd1 [20,21,22,23], partially normalized the accumulation of toxic saturated VLCFA levels in X-ALD fibroblasts and male Abcd1-deficient (Abcd1–/y) mice [19]. Vice versa, CRISPR knockout of Scd1 mimicked the motor phenotype observed in Abcd1 zebrafish mutants. These findings are consistent with exposure to saturated, but not monounsaturated, VLCFAs inducing ER stress and perturbing oxidative stress homeostasis and mitochondrial function in human X-ALD fibroblasts [24,25,26,27]. Notably, analysis of liver histology of wild-types and Abcd1–/y mice treated with the LXR agonist T0901317 also showed adverse effects, including liver steatosis, cell ballooning, and active inflammation [28]. While this study identified the importance of SCD1 in preventing the toxic accumulation of saturated VLCFAs, more research is warranted to confirm the therapeutic potential of increasing SCD1 expression in X-ALD and to assess the suitability of LXR agonists to do so. For example, it would be valuable to assess whether treatment with tissue- or isoform-specific LXR agonists [28], or other SCD1 modulators with reduced toxicity, can impact axonal degeneration in X-ALD without causing adverse side effects in the liver. More research is also needed to elucidate the molecular mechanisms underpinning the impact of LXR modulators on VLCFA quality. While LXR activation is indeed a driver of SCD1 expression, the endogenous LXR agonist 25-hydroxcholesterol is also reported to reduce saturated VLCFAs in X-ALD fibroblasts and oligodendrocytes by decreasing the expression of VLCFA elongase 1 (ELOVL1) [29]. Further, LXR activation can reduce ABCD2 and ABCD3 abundance, which represent essential compensatory enzymes for lack of ABCD1 [30]. Hence, the protective impact of LXRs on SCD1 abundance may be nullified by a simultaneous decrease in ABCD2 and ABCD3 activity. Notably, alongside increasing ABCD2 and ABCD3 [31], fibrates increase SCD1 expression through activation of peroxisome proliferator-activated receptor (PPAR) α and sterol regulatory element-binding protein (SREBP)1c [32], and therefore could represent an alternative therapeutic approach to simultaneously promote peroxisomal β-oxidation of VCLFAs and the metabolic rerouting of saturated to monounsaturated VLCFAs in X-ALD [33]. Finally, cell type-dependent and conditional differences in SCD1 expression and activity, as well as the SFA/MUFA balance, might well impact the functional properties of fibroblasts, neurons, and glial cells in X-ALD differently. In support of this notion, while being protective in X-ALD fibroblasts, increased SCD1 activity in multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) is associated with the formation of disease-promoting microglia and neuronal dysfunction (see Sect. 3.2–3.4). Hence, in-depth profiling of cellular differences in response to changes in the abundance of SFA, MUFA, and VLCFAs, as well as the activity of ABCD1 and SCD1, is likely to provide increased insight into X-ALD disease pathology.

MS is a neurodegenerative disease of the CNS that is fueled by an unequivocal autoimmune response directed against CNS-derived antigens. While genetic predisposition accounts for part of the disease risk [34], a range of lifestyle and environmental factors also play a critical role in disease progression (reviewed in [35]). Key players in the immune response in MS include autoreactive T cells which cross the blood-brain barrier (BBB) and trigger inflammation. This leads to the CNS infiltration and activation of additional immune cells, including macrophages and microglia, resulting in demyelination and axonal loss [36]. While endogenous CNS repair processes such as remyelination are apparent in early MS lesions, they frequently fail in progressive forms of MS. This has profound pathophysiological consequences as sustained loss of myelin disrupts axonal integrity and increases the susceptibility of axons to inflammatory mediators [37]. With neurodegeneration standing as the primary catalyst for MS disease symptoms, these studies accentuate the significance of unraveling the cellular and molecular drivers of failure of CNS repair in MS.

Growing evidence from preclinical models that mimic autoimmunity-mediated demyelination and remyelination highlights that imbalances in FA metabolism and levels drive MS disease pathology by regulating the inflammatory and regenerative properties of immune cells (reviewed in [1]). Of particular interest, SCD1 abundance and activity are highly elevated in macrophages and microglia in active brain lesions of MS patients, and loss and inhibition of SCD1 improves brain repair in toxin-induced ex vivo and in vivo models for demyelination [38]. Mechanistically, SCD1-generated MUFAs were demonstrated to reduce the surface abundance of cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) in a protein kinase C (PKC) δ-dependent manner. Loss of ABCA1 enhanced the intracellular accumulation of highly inflammatory free cholesterol in foamy myelin-containing macrophages and microglia, thereby promoting the induction of an inflammatory, disease-promoting phagocyte phenotype (Fig. 1). These findings are consistent with previous studies showing that MUFAs can destabilize membrane ABCA1 and inhibit ABCA1-mediated cholesterol efflux [39,40,41,42]. The authors further showed that activation of LXRs by myelin-derived cholesterol, LXRβ in particular, increased SCD1 expression in macrophages and microglia after sustained intracellular accumulation [38, 43]. Collectively, these findings provide a molecular rationale for the progressive nature of demyelinating lesions in MS and identify SCD1 as a promising therapeutic target to promote remyelination. Nevertheless, in light of the deleterious consequences associated with heightened SCD1 activity in foam cells, further investigation is essential to elucidate the underlying molecular basis for the escalated SCD1 activity in these cells. In particular, the findings emphasize the crucial role of continuous endogenous LXRβ activation and subsequent SCD1 induction in driving the formation of inflammatory foam cells in MS, despite the prevailing assumption that LXR activation suppresses the formation of inflammatory macrophage and microglia subsets (reviewed in 44). While these findings could be contingent on specific cellular and environmental differences, they align with existing evidence that prolonged LXR activation, in contrast to short-term activation, can elicit inflammatory responses in human macrophages [43]. Furthermore, since the expression levels of Scd1 transcripts are notably elevated in mature myelin-forming oligodendrocytes compared to their precursor cells [45], it is imperative to undertake a more in-depth investigation into the consequences of inhibiting SCD1 in this specific cell population as well.

Alongside suppressing remyelination by promoting the induction of an inflammatory phagocyte phenotype, more recent findings indicate an important role for SCD1 in autoimmune-mediated demyelination in MS as well, with patient-derived T cells displaying enhanced SCD1 activity [46]. Pharmacological inhibition and genetic deficiency of SCD1 was further found to reduce autoimmune-mediated demyelination in the experimental autoimmune encephalomyelitis (EAE) model, a well described animal model for MS that mimics autoimmune-mediated degenerative events in the CNS [47]. Mechanistically, loss and inhibition of SCD1 primed naïve CD4+ T cells to differentiate into immunosuppressive regulatory T cells (Tregs). Guided by RNA sequencing and lipidomics analysis, absence of SCD1 in T cells was found to enhance hydrolysis of TGs and phosphatidylcholine through adipose triglyceride lipase (ATGL). This process culminated in the release of docosahexaenoic acid (DHA), an omega-3 PUFA, which, in turn, augmented Treg differentiation and diminished CNS pathology in EAE mice by activating the nuclear receptor PPARγ (Fig. 1) [46]. Intriguingly, the latter finding suggest a reciprocal interaction between SCD1 and PPARγ, where SCD1 is not merely a responsive gene of PPARγ but also contributes to the continuous activation of PPARγ [48]. All in all, this study provides evidence that SCD1 acts as an endogenous brake on the differentiation of Tregs, thereby likely contributing to autoimmune-mediated demyelination and neuroinflammation in the EAE model. Although these findings align with previous observations showing that (1) absence of SCD1 heightens splenic follicular Tregs after influenza immunization [49], (2) ATGL favors the hydrolysis of TGs and phosphatidylcholine rich in PUFAs [50], (3) DHA is a potent endogenous ligand for PPARγ [51], and (4) both DHA and PPARγ promote Treg differentiation and suppress neuroinflammation [51,52,53,54,55,56,57,58], several unanswered questions persist. For example, in contrast to promoting the differentiation of immunomodulatory Tregs in the EAE model, absence of SCD1 has also been reported to enhance the colitogenic potential of Scd1−/− CD4+CD25− T cells when transplanted into Rag1−/− mice [59], an immunodeficient mouse model lacking mature T and B cells. Deficiency of Scd1 led to elevated levels of SFAs, resulting in an enhanced secretory profile of effector T cells and, unexpectedly, an increased cellular membrane fluidity. While differences in the experimental animal models used may account for this discrepancy, it also raises the intriguing question of whether increased Treg differentiation serves as a protective response against the concurrent induction of the colitogenic potential in T cells deficient in Scd1. In addition, the precise molecular mechanisms driving increased ATGL-dependent release of DHA in T cells lacking SCD1 await further elucidation. While it could signify a compensatory mechanism aimed at maintaining sufficient cellular MUFAs, ATGL-mediated liberation of free DHA could also ensue to safeguard T cells against ER stress and cellular inflammation triggered by elevated SFA levels, potentially through the activation of PPARγ [60, 61]. Supporting this hypothesis, dietary supplementation with ω-3 PUFAs has been shown to mitigate the side-effects associated with SCD1 inhibition in Ldlr−/−ApoB100/100 mice, including the acceleration of atherosclerosis, lipoprotein abnormalities, and heightened toll-like receptor 4 (TLR4) sensitivity [62]. All in all, these intriguing discrepancies and molecular mechanisms associated with SCD1 deficiency merit further exploration.

AD is a neurodegenerative disorder characterized by a progressive decline in cognitive function, driven by complex pathological mechanisms that involve the accumulation of amyloid β (Aβ) plaques and hyperphosphorylated tau tangles. These hallmark protein aggregates initiate widespread neuronal damage, synaptic dysfunction, and eventually neuronal loss, leading to brain atrophy and impaired neural networks (reviewed in [63]). Next to these classical pathological features, numerous studies highlight a central role of neuroinflammation, vascular dysfunction, and mitochondrial impairment, in AD pathology (reviewed in [64]). Moreover, neural stem cell (NSC) dysfunction is associated with AD [65,66,67,68,69], with NSC proliferation, differentiation, and migration being disrupted by Aβ and tau proteins [70, 71].

Metabolic disturbances are increasingly recognized as key contributors to AD pathology, highlighted by significant alterations in brain lipids in AD patients and genetic risk factors associated with lipid metabolism, including APOE, TREM2, APOJ, PICALM, ABCA1, and ABCA7 (reviewed in [72]). Notably, few studies found that SCD1 activity and expression is increased in plasma and brains of AD patients, and is associated with disease progression and decreased cognitive performance [73,74,75,76,77]. In support of enhanced SCD1 activity, post-mortem AD brains and triple-transgenic AD (3xTg-AD) mice demonstrate an accumulation of MUFA-enriched TGs within ependymal cells in the subventricular zone (SVZ) lining the ventricles, with the majority of TGs being enriched in SCD1-derived MUFAs such as OA [78]. This increase in MUFA-enriched TGs in SVZ ependymal cells was found to perturb NSC proliferation in the SVZ in a paracrine manner via soluble mediators (Fig. 1). Locally increasing OA in wild-type mice recapitulated the AD-associated ependymal TG phenotype and impaired NSC expansion. Mechanistically, OA inhibited NSC expansion by promoting hyperactivation of the AKT signaling pathway, which is consistent with SCD1 driving AKT Ser473 phosphorylation and activation in cancer cells [79, 80]. In support of the disease-promoting impact of SCD1-generated MUFAs in AD, intraventricular infusion with an SCD1 inhibitor reduced the accumulation of MUFA-rich TGs and rescued early NSC dysfunction in periventricular and hippocampal regions in pre-symptomatic 3xTg-AD mice [78]. The latter findings point towards a key role of SCD1 in controlling TG accumulation and SVZ NSC dysfunction in AD, and argues for SCD1 inhibitors being a promising therapeutic tool to attenuate early pathological hallmarks in AD. Nevertheless, observed disturbances in SVZ lipid metabolism and the impact on NSC activity also raise a number of mechanistic questions [81]. First, the root cause of the disturbances in FA metabolism and subsequent NSC dysfunction in 3xTg-AD mice remains enigmatic. It could stem from AD genetic mutations directly, represent a non-specific response to the stress AD imposes on the brain, or serve as a secondary consequence of other AD-related pathologies. With respect to the latter, although Hamilton et al. showed that impairments in neurogenesis in the 3xTg-AD mouse model occur prior to the accumulation of Aβ and tau tangles [82], other studies found that Aβ and tau can interfere with NSC function and neurogenesis [70, 71]. Hence, it remains unclear whether the disturbances in FA metabolism and subsequent NSC dysfunction are linked to Aβ and tau pathology, highlighting the need for further research. Secondly, the cellular targets and molecular mechanisms of the SCD1 inhibitor responsible for alleviating neurogenic defects in 3xTg-AD mice remain unclear. In this respect, despite the adverse effects of heightened OA levels and SCD1 activity on NSC physiology in the SVZ, OA also plays a pivotal role in promoting NSC survival within the dentate gyrus and can instigate hippocampal NSC neurogenesis [83]. This duality underscores the complexity of lipid metabolism’s impact on NSCs in various brain regions during disease progression. Lastly, the specific FA species responsible for perturbed NSC physiology in the SVZ during AD remain to be conclusively identified. While OA may contribute significantly, it is possible that the disruption also involves downstream PUFAs, or a combination of both MUFA and PUFA species.

In a follow-up study, the authors demonstrated that SCD1 inhibition also reverses deficits in spatial learning and memory in symptomatic 3xTg-AD mice [84]. Here, improved cognitive performance was associated with a reduced inflammatory activation of microglia and improved dendritic spine number and structure. When considering alterations in microglial function in AD, an intriguing parallel emerges with MS. Specifically, akin to the uptake of myelin by MS-associated microglia [38], the endocytosis of Aβ elevates SCD1 expression in microglia [85], and absence of SCD1 triggers an advantageous microglia phenotype in both AD and MS (Fig. 1). Interestingly, SCD1 inhibition did not impact NSC activity in symptomatic 3xTg-AD mice, nor did it impact other key AD hallmarks such as Aβ accumulation, tau aggregation, or neuronal loss. Although the exact molecular mechanisms behind this discrepancy remain unclear, previous research has shown that synaptic loss and memory can be restored in AD mouse models without a reduction in Aβ levels [86,87,88]. It is worth noting that the authors showed that SCD1 inhibition substantially reduced Mhc-I gene expression in activated microglia within 3xTg-AD mice [84]. Given the association of MHC-I with synaptic pruning, learning, and memory [89,