Ulcerative colitis (UC) and Crohn's disease (CD) are the two most common forms of inflammatory bowel disease (IBD), which is identified by a lack of specificity and a prolonged inflammation of the intestines that has no known cause [1]. Although the precise causes and pathogenesis of UC remain unclear, it is widely believed to be an imbalance of the gut microbiota, environmental factors, genetic factors, and neuroendocrine dysfunctions caused by psychological factors, as well as impaired intestinal barrier function and immune system dysregulation [2], [3], [4], [5], [6]. Despite advances in understanding these factors, existing treatments provide limited relief, and many UC patients continue to suffer from severe complications, including gastrointestinal obstruction, perforation, bleeding, abscess formation, fistula development, and an increased risk of colorectal cancer [7]. With UC emerging as a global health concern, individuals’ health and quality of life are increasingly compromised. Consequently, the development of more potent UC treatments is urgently needed.

Mesenchymal stem cells (MSCs) have the remarkable ability to self-renew and differentiate into a wide range of cell types. In addition to their capacity for regeneration, they have strong immunomodulatory effects that inhibit the function of immune cells such as natural killer cells, T cells, and B cells [8], [9], [10], [11]. The primary mechanism underlying this immunomodulation is the nonspecific antiproliferative effect resulting from the inhibition of cyclin D2 [12]. MSCs can be extracted from a variety of tissues, such as bone marrow, fat, menstrual blood, endometrial polyps, and umbilical cord tissue. In contrast to MSCs, menstrual blood-derived endometrial regenerative cells (ERCs) offer a novel alternative with comparable functions and additional benefits, such as simplicity, safety, non-invasiveness, and lower cost [13]. Despite these advantages, challenges remain in the systemic administration of ERCs. When injected intravenously, ERCs are often intercepted by the pulmonary barrier, which hinders their delivery to inflamed tissues and poses a risk of pulmonary embolism [14].

MSC-secreted exosomes have potential medical use. These 40–160 nm diameter nanoscale vesicles [15] transport proteins, lipids, messenger RNA (mRNA), and non-coding RNA (ncRNA) to promote intercellular communication [16], [17]. Our previous research found that ERC-derived exosomes (ERC-Exos) also retained the immunomodulatory properties of ERCs. For example, Zhu et al. revealed that ERC-Exos could attenuate colitis by downregulating intestinal epithelial cell ferroptosis [18]. This characteristic makes exosomes a potential “cell-free” treatment strategy, overcoming the drawbacks of conventional cell-based treatments. Thus, exosomes represent a promising therapeutic approach, leveraging the benefits of ERCs without the challenges of cell delivery and introducing a new paradigm in stem cell medicine.

SIRT6, a crucial NAD+ -dependent enzyme in the sirtuin family, is essential for a number of cellular functions, including ageing, metabolic balance, DNA repair, and inflammatory regulation [19], [20], [21]. Its anti-inflammatory effects are particularly significant, as it suppresses inflammatory cytokine expression by deacetylating the NF-kB signaling pathway, playing a key role in managing chronic inflammation and autoimmune diseases [22], [23]. SIRT6 plays an anti-aging role by alleviating the accumulation of chronic inflammation through its antioxidant stress capacity [24], [25]. Similarly, Liu et al. found that SIRT6 maintained R-spondin-1 expression and enhanced the intestinal epithelium's resistance to injury in mice, highlighting its protective role in colitis [26]. SIRT6 plays therapeutic roles in alleviating kidney damage in diabetic patients, promoting the resolution of periodontal inflammation, improving neuroinflammation and brain injury, reducing foam cell formation, and mitigating atherosclerosis [27], [28], [29], [30], [31]. These therapeutic effects are closely associated with the regulation of macrophages. Given that UC progression is tightly linked to dysfunctional macrophage polarization, we investigated whether SIRT6 could alleviate UC by regulating macrophages.

Exosomes have demonstrated efficacy in UC treatment [18], but the role of SIRT6 in mediating their immunomodulatory effects against colitis remains unexplored. Prior research has highlighted SIRT6’s therapeutic value across various inflammatory conditions. For instance, Liu et al. investigated that exosomes derived from Sirt6-enhanced adipose stem cells could open new epigenetic pathways in treating myocardial ischemia-reperfusion injury [32]. Similarly, Wei et al. demonstrated that bone marrow MSC exosomes inhibit aortic calcification caused by phosphate, a process driven by SIRT6's deacetylation of HMGB1 [33]. Given the promising immunomodulatory potential of SIRT6, its role within exosomes has been proposed for exploration. Therefore, this research aimed at investigating whether the therapeutic benefits of ERC-Exos were mediated by SIRT6 and whether SIRT6-expressing ERC-Exos worked by modulating macrophage polarization in UC.