Chang Liu

The pathogenesis of colorectal cancer (CRC) is complicated, as evidenced by the intensive crosstalk between cancer cells and the gut microbiota. The inflammatory microenvironment surrounding cancer cells accelerates the reproduction of pathogenic bacteria, and the polyketide synthase‐catalyzed metabolites generated by these bacteria correspondingly promote cancer cell proliferation, thus forming a detrimental cancer‐bacteria cycle. Here, we demonstrated that gasdermin‐D (GSDMD) (the executive protein of cell pyroptosis) improves gut dysbiosis in an obese mouse model, whereas GSDMD deficiency promotes CRC development in these mice, thus suggesting that GSDMD is a potential target for CRC therapy. In this study, we designed a novel dual‐targeted GSH‐sensitive nanodrug delivery system aimed at specifically delivering mRNA encoding the N‐terminal domain of GSDMD (GSDMD‐N mRNA) to local CRC tissues. Such a system helps to induce pyroptosis in CRC cells and corrects gut dysbiosis caused by the tumor microenvironment, thus achieving a dual regulatory effect. This study contributes to the current understanding of the pathophysiological functions of GSDMD‐mediated pyroptosis in CRC and suggests a new strategy for precise CRC therapy targeting GSDMD, thereby providing a solid theoretical basis and experimental evidence for the development of mRNA nanodrug delivery systems.

The circadian rhythm and lipid metabolism in organisms are tightly coupled, yet the role of lncRNAs in the integration of these two important physiological processes remains unclear. In this study, we identified a liver-specific lncRNA named HlncRNA-1, which regulates lipid metabolism while responding to circadian rhythms. Mice overexpressing HlncRNA-1 exhibited suppressed liver fat accumulation under conditions of both nutrient surplus and deficiency, along with improved insulin sensitivity. At the molecular level, ChIP assays demonstrate that Dhx9 directly occupies the HlncRNA-1 promoter, tethering circadian clock signals to this lncRNA. HlncRNA-1 subsequently recruits Hdlbp to coordinate hepatic lipid catabolism. In summary, HlncRNA-1 serves as a regulatory conduit that translates circadian clock cues into metabolic outputs, orchestrating circadian control of hepatic lipid metabolism, and activating this lncRNA represents a viable target for precisely intervening in lipid metabolic disorders induced by circadian disruption. The alternative text for this image may have been generated using AI.

The increasing prevalence of artificial light sources has rendered blue light (BL) a novel environmental metabolic disruptor. This study aimed to investigate the potential effects of BL exposure on mitochondrial function in the adipose tissue of high-fat diet (HFD) mice. A total of 36 mice were divided into the normal diet (ND) and HFD groups and subsequently exposed to white light (WL) and BL. Body weight was monitored regularly, and glucose tolerance and insulin sensitivity were assessed using intraperitoneal glucose tolerance tests (IPGTT) and intraperitoneal insulin tolerance tests (IPITT). Body fat was measured using nuclear magnetic resonance, and overall energy metabolism was evaluated using a metabolic energy monitoring system. After the mice were humanely sacrificed, inguinal white adipose tissue (iWAT), epididymal white adipose tissue (eWAT), and brown adipose tissue (BAT) were collected for weighing, histological analysis, and serum biochemical analysis. Oxidative stress indicators were detected by flow cytometry and other methods. We found that, in HFD-fed mice, BL exposure significantly increased body weight and body fat, exacerbated insulin resistance, and reduced oxygen consumption and thermogenesis. Transcriptomic analysis revealed that BL exposure induced oxidative stress in the white adipose tissue and suppressed the oxidative phosphorylation pathway. RT-qPCR and western blotting of the iWAT confirmed the downregulation of key genes in this pathway. Collectively, our results suggest that BL may target the adipose tissue, trigger oxidative stress, suppress oxidative phosphorylation, impair mitochondrial function, and exacerbate obesity.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a severe public health crisis, affecting more than a quarter of the adult population. ANGPTL8 is a potential therapeutic target for MASLD owing to its dual roles in lipid and inflammatory regulation. However, current targeting strategies are inadequate, particularly in the realm of natural compound-driven protein degradation inducers. In this study, we utilize molecular docking analysis, a cellular thermal shift assay, a drug affinity responsive target stability assay, and a surface plasmon resonance assay to identify Crocin II as a potential candidate for targeting ANGPTL8. We demonstrate that Crocin II can facilitate the degradation of ANGPTL8 protein via the autophagosome-lysosome pathway. Pharmacodynamically, Crocin II ameliorates HFD-induced MASLD by targeting ANGPTL8, with no overt adverse effects in murine kidneys, hearts, and spleens. In conclusion, our study demonstrates that Crocin II has a favorable therapeutic effect on MASLD by targeting ANGPTL8 and promoting its protein degradation, indicating that Crocin II is a promising candidate for MASLD therapy.

Obesity‐induced insulin resistance is a hallmark of metabolic syndrome, and chronic low‐grade inflammation links obesity to insulin resistance through the activation of tissue‐infiltrating immune cells. Current treatments are lacking in efficacy and immunosuppression. Therefore, novel therapies are needed to prevent chronic inflammation and alleviate obesity‐related insulin resistance. In this work, novel red light‐responsive biomimetic nanoparticles (RSCP NPs) are reported to perform targeted delivery of multiple drugs and effectively reduce nonspecific enrichment. These results showed that the dual‐targeting and multiple‐signaling response (red light signaling and different pH microenvironments) of the RSCP NPs enabled the precise delivery of astaxanthin (Asta) and rosiglitazone (Rosi) to M1‐like macrophages and white adipocytes, respectively, to alleviate the low‐grade inflammation of white adipose tissue (WAT) and promote white adipocyte browning. Moreover, RSCP NPs‐mediated Asta and Rosi treatment robustly alleviated insulin resistance and other metabolic disorders in the obese animal models (high‐fat diet (HFD)‐induced or genetically obese mice). Overall, this study provides a theoretical and practical basis for the development and application of novel drug delivery systems for metabolic diseases by elucidating the synergistic long‐term targeting mechanism and target molecule stability of red light‐sensitive bionic nanodrug delivery systems.

Specific wavelengths and intensities of light offer potential for modulating mitochondrial function to influence aging which is important for the development of non-invasive and modifiable exogenous anti-aging tools. However, the effects of exposure to different wavelengths of light during the early stages of life on health in adulthood, and the underlying mechanisms, remain poorly understood. In this study, we utilized Caenorhabditis elegans to investigate the effects of early-life (L1 to young adult stage) exposure to different light wavelengths (white, red, blue, green) on healthspan. We found that red light exposure (630 nm, 200 lx) during early life extended lifespan by 10.34% without affecting growth, movement, or reproduction, and improved late-life health indicators. Importantly, it significantly enhanced healthspan in later life, suggesting its potential as a non-invasive anti-aging strategy. Mechanistically, red light transiently suppressed mitochondrial bioenergetic activity, biogenesis, and membrane potential, and altered mitochondrial dynamics. Upon light withdrawal, mitochondrial function progressively recovered, demonstrating enhanced structure and function by day 6. Furthermore, red light stimulated ROS production, activated AMPKα phosphorylation, and triggered downstream mitochondrial quality control (MQC) programs, including the unfolded protein response (UPR^MT) and mitophagy. Notably, these protective effects were conserved in human dermal fibroblasts, suggesting the translational applicability of this pathway. Collectively, our study identifies a specific “photophysiological window” during early life through which red light promotes longevity via ROS-mediated activation of AMPK and enhancement of MQC, proposing a non-invasive, safe, evolutionarily conserved, and drug-free strategy to mitigate age-related mitochondrial decline. Therefore, red light can serve as a non-invasive anti-aging strategy to enhance healthspan and potentially alleviate age-related mitochondrial dysfunction.

With papillary thyroid carcinoma (PTC) rates rising significantly, concerns about conventional treatments like thyroidectomy and radiotherapy highlight the need for non‐invasive options. Our study explores photobiomodulation therapy (PBMT), which uses specific light wavelengths to evoke cellular responses in PTC treatment. Our research utilized a custom‐designed optical system to investigate PBMT, finding that blue light at a wavelength of 465 nm can safely and effectively inhibit the proliferation of the TPC‐1 PTC cell line by inducing cell cycle arrest. Additionally, we developed a wirelessly powered wearable PBMT device, which is equipped with an advanced light delivery system that ensures precise and consistent dosage. This device designed for optimal patient comfort, effectively suppressed tumor growth in mouse models without adverse effects. PBMT indicates thyroid tissue's light responsiveness as a non‐visual organ. Our study's innovative approach integrates the disciplines of oncology, biophysics, and medical device technology, thereby advancing the treatment paradigms for PTC. This interdisciplinary bridge not only highlights our groundbreaking findings but also paves the way for future research in cancer therapy and photomedicine.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, with a rising incidence. Traditional treatments, such as thyroidectomy and radiotherapy, often lead to significant side effects, including impaired thyroid function. Therefore, there is an urgent need for non-invasive therapeutic approaches. This study aims to explore the potential of photobiomodulation therapy (PBMT), a non-invasive treatment using specific wavelengths of light, in the management of PTC. We investigated the effects of blue light PBMT on PTC cells, focusing on the Retinal-OPSIN 3 (OPN3) complex’s role in mediating cellular responses. Blue light exposure was applied to PTC cells, and subsequent changes in cellular proliferation, cell cycle progression, and protein expression were analyzed. Statistical tests, including one-way ANOVA and t-tests, were used to evaluate the significance of the findings. Blue light exposure led to the dissociation of 11-cis-retinal from OPN3, resulting in the accumulation of all-trans retinal. This accumulation disrupted cellular proliferation pathways and induced G0/G1 cell cycle arrest in PTC cells. The Retinal-OPN3 complex was found to be a key mediator in these processes, demonstrating that thyroid cells can respond to specific light wavelengths and utilize their photoreceptive potential for therapeutic purposes. Our findings suggest that PBMT, through the modulation of the Retinal-OPN3 complex, offers a promising non-invasive approach for treating PTC. This study highlights the therapeutic potential of light signal transduction in non-ocular tissues and opens new avenues for non-invasive cancer therapies.

Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP. Here, by developing a Cy5-modified single-strand DNA-aptamer-based approach targeting DEHP, we have identified luteolin as a potential drug, which showcasing robust efficacy in detoxifying the DEHP by facilitating the expulsion of DEHP in both mouse primary hepatocytes and livers. Mechanistically, luteolin enhances the protein degradation of hepatic urocanate hydratase 1 (Uroc1) by targeting its Ala270 and Val272 sites. More importantly, trans- urocanic acid ( trans- UCA), as the substrate of Uroc1, possesses properties similar to luteolin by regulating the lysosomal exocytosis through the inhibition of the ERK1/2 signal cascade. In summary, luteolin serves as a potent therapeutic agent in efficiently detoxifying DEHP in the liver by regulating the UCA/Uroc1 axis.