SIRT1 regulates the activity of glucocorticoids, while glucocorticoids also influence the expression of SIRT1. Dexamethasone reduces SIRT1 expression and enzymatic activity by inducing miR-128, which is known to directly target SIRT1 in pig preadipocytes (26). Furthermore, dexamethasone-induced expression of miR-34a can suppress SIRT1 deacetylase activity, led to decreased dexamethasone-induced cell death responses in malignant multiple myeloma cells (27). In mesenchymal stem cells, dexamethasone treatment for 24 h reduced SIRT1 expression (28). Moreover, in rats with adjuvant-induced arthritis, glucocorticoid treatment reduced the increase in SIRT1 expression and accompanying inflammation in PBMCs and liver (29). These studies indicate that glucocorticoid treatment down-regulates SIRT1 expression, which could further impair glucocorticoid activity in certain diseases.

Growing evidence suggests that SIRT1 regulates steroid hormone receptor activity. SIRT1 generally inhibits androgen receptor (AR), estrogen receptor (ER), and mineralocorticoid receptor (MR) activity (30), but has different effects on glucocorticoid signaling activity. Prednisolone is reported to inhibit adriamycin-induced vascular smooth muscle cell senescence and inflammation through the SIRT1-AMP-activated protein kinase(AMPK)signaling pathway (31), with down-regulation of SIRT1 augmenting the effects of prednisolone on inflammation and senescence, and up-regulation of SIRT1 attenuating the effects on cellular senescence. Furthermore, SIRT1 promotes glucocorticoid induced anti-inflammatory activity but inhibits uncoupling protein-3 (UPC3) gene transcription, a mitochondrial membrane transporter induced by glucocorticoid that protected skeletal muscle cells from oxidative stress damage (32). Thus, these studies suggest that SIRT1 exerts variable functions on glucocorticoid signaling under different conditions.

Side effects associated with glucocorticoid treatment include osteoporosis, decreased bone mineral content, and reduced bone tissue absorption. Recent study has shown that ferulic acid can protect against dexamethasone-induced osteoporosis in neonatal rats by up-regulating SIRT1 gene and protein expression and reducing nuclear factor-κB (NF-κB) activation (33). Furthermore, nicotinamide mononucleotide treatment has been shown to attenuate dexamethasone-induced osteogenic inhibition by promoting SIRT1 and peroxisome proliferator activated receptor gamma coactivator (PGC)-1α expression, while knockdown of SIRT1 reverses the protective effects of nicotinamide mononucleotide and the expression of PGC-1α (34). Dexamethasone can also induce extracellular matrix loss in chondrocytes isolated from mouse knee joints, while melatonin pretreatment reverses the negative effects of dexamethasone via mediation of the SIRT1 pathway and inhibition of SIRT1 by the inhibitor EX527 reverses the protective effects of melatonin (35). In a cellular model of corticosterone-induced neurotoxicity, d-limonene shows neuroprotective effects through up-regulation of SIRT1, thereby suppressing NF-κB nuclear translocation and inhibiting inflammatory factors (36). Thus, these results indicate that SIRT1 can suppress glucocorticoid-induced side effects ( Figure 3 ).

Unliganded GR is primarily localized in the cytoplasm in complex form, where it binds with heat shock proteins, immunophilins, and other molecular chaperones. Aberrant GR expression or nuclear translocation is associated with glucocorticoid insensitivity. For example, airway smooth muscle cells from patients with severe asthma exhibit reduced GR expression and impaired nuclear translocation associated with reduced glucocorticoid sensitivity (4). We previously found that decreased GR expression and impaired nuclear translocation in respiratory syncytial virus-infected cells and mice led to glucocorticoid insensitivity (37, 38). Notably, respiratory syncytial virus nonstructural protein 1 (NS1) competitively inhibits GR binding to nucleocytoplasmic transporter 13, resulting in GR cytoplasmic retention (37).

SIRT1 can influence the transcriptional activity of AR (39) as well as enhance GR-induced transcriptional activity through physical interactions. Notably, SIRT1 cooperates with GR to bind to the glucocorticoid response element-induced glucocorticoid-responsive genes (9). Knockdown of SIRT1 influenced up to 30% of the glucocorticoid-responsive genes. SIRT1 has also been shown to interact with GR in a glucocorticoid-dependent manner in rats under estradiol benzoate withdrawal (10). Furthermore, activation of hippocampal SIRT1 has been shown to block the development of postpartum depression-related to increased GR(GRα) expression (10).Thus, SIRT1 may be a novel target for the treatment of postpartum depression. In GT1–7 cells, SIRT1 knockdown using small interfering RNAs significantly suppressed GRα expression and reduced GRα protein levels (40). In contrast, GRβ, which functions as a dominant-negative inhibitor of GRα, has been reported to be elevated in corticosteroid-resistant patients with asthma, COPD, and RSV bronchiolitis (41–43). Previous studies have demonstrated that intrauterine growth retardation significantly increases H3K9 acetylation at the GRβ exon region, leading to upregulated GRβ expression in the rat hippocampus (44). Notably, H3K9 is a known deacetylation target of SIRT1 (45).It suggested that SIRT1 might play a role in the suppression of GRβ expression. However, it is important to note that there is currently no direct evidence no direct evidence to substantiate the claim that SIRT1 suppresses GRβ expression. The relationship between them and their role in glucocorticoid resistance still warrants further investigation.

Recent study has shown that hyperacetylation of Hsp90 which activity is required for the maintenance of GR stability blocks GR nuclear translocation in INS-1 cells reversed dexamethasone effect on insulin secretion (46). Deacetylation of Hsp90 at K294 by SIRT2 overexpression results in disassociation of Hsp90 with GR and subsequent nuclear translocation (47), thereby repressing inflammatory cytokine expression. There were no reports about SIRT1 interacted with Hsp90 yet while the potential ability exist.

Post-translational modification of GR plays an important role in regulating the biological actions of glucocorticoids. GR is acetylated by CLOCK at lysine residues 494 and 495 within the hinge region, which reduces the binding affinity of GR to DNA elements as well as its ability to regulate transcription (48). The deacetylation of GR by histone deacetylase 2 is required for efficient transrepression of NF-κB-regulated genes (49). While, SIRT1 interacted with GR whether could deacetylate these lysines residues and change the GR activity still need further investigation but the potential ability exist ( Figure 4 ).

Helper T cells exhibit distinct sensitivities to glucocorticoids, which significantly influence their survival, differentiation, and cytokine production. Therefore, investigating the expression and regulatory role of SIRT1 in T cell subsets is of significant importance.SIRT1 is highly expressed in immune cells, and the expression levels are nearly equivalent among helper T cell subsets. Figure 5 shows RNA expression levels in different T cell subsets (from the Human Protein Atlas). The expression is highest in naive T-reg cells and lowest in T-reg cells. It seems that as T cells become activated, the expression of SIRT1 decreases accordingly.

Accumulating evidence highlights the important role of SIRT1 in glucocorticoid-resistant diseases. SIRT1 single-nucleotide polymorphisms are associated with glucocorticoid sensitivity in primary immune thrombocytopenia (69). Furthermore, CC/TC genotypes of SIRT1 rs12778366 show a two-fold increase in the risk of glucocorticoid resistance (70). CD8⁺ T and natural killer T cell(NKT)-like cells in patients with chronic obstructive pulmonary disease (COPD) show glucocorticoid resistance associated with decreased SIRT1 expression (71). Treatment with SIRT1 activators restores the anti-inflammatory activity of prednisolone and reduces pro-inflammatory cytokine production (72). Glucocorticoids are also widely used to treat B acute lymphoblastic leukemia, although their efficacy is often impaired by the development of resistance (73). FOXO3a translocates into the nucleus to mediate the cytotoxic function of dexamethasone, and SIRT1/2-mediated acetylation of Lys-242/5 is associated with dexamethasone-induced FOXO3a activity (73). Human peripheral blood mononuclear cells (PBMCs) from patients with severe asthma show reduced SIRT1 protein expression and activity and increased Th2 cytokine expression (74); and treatment of HUT78 T-cells with SIRT inhibitors can increase GATA Binding Protein 3(GATA-3) acetylation and IL-4 and IL-13 expression (75). However, severe asthmatics appear to be largely unresponsive to high-dose inhaled and systemic glucocorticoids (76). While direct evidence showing an association between SIRT1 and glucocorticoid resistance in asthma is still lacking, studies have demonstrated that SIRT1 plays a critical role in suppressing allergic airway inflammation in vivo and in vitro (77).