The decrease in fibroblast collagen is a primary contributor to skin aging. Lactate can participate in collagen synthesis through lysine lactylation by regulating gene transcription. However, the precise mechanism by which lactate influences collagen synthesis requires further investigation. This study demonstrates that the depletion of macrophages mitigates the stimulating effect of lactate on collagen synthesis in fibroblasts. Through joint CUT&Tag and RNA‐sequencing analyses, a feedback loop between H4K12 lactylation (H4K12la) and histone deacetylase 3 (HDAC3) in macrophages that drives lactate‐induced collagen synthesis are identified. Macrophages can uptake extracellular lactate via monocarboxylate transporter‐1 (MCT1), leading to an up‐regulation of H4K12la levels through a KAT5‐KAT8‐dependent mechanism in response to Poly‐L‐Lactic Acid (PLLA) stimulation, a source of low concentration and persistent lactate, thereby promoting collagen synthesis in fibroblasts. Furthermore, H4K12la is enriched at the promoters of TGF‐β1 and TGF‐β3, enhancing their transcription. Hyperlactylation of H4K12la inhibits the expression of the eraser HDAC3, while the activation of HDAC3 reduces H4K12la in macrophages and suppresses collagen synthesis in fibroblasts. In conclusion, this study illustrates that macrophages play a critical role in lactate‐induced collagen synthesis in the skin, and targeting the lactate‐H4K12la‐HDAC3‐TGF‐β axis may represent a novel approach for enhancing collagen production to combat skin aging.

The core catalytic unit of telomerase comprises telomerase reverse transcriptase (TERT) and telomerase RNA (TERC). Unlike TERT, which is predominantly expressed in cancer and stem cells, TERC is ubiquitously expressed in normal somatic cells without telomerase activity. However, the functions of TERC in these telomerase-negative cells remain elusive. Here, we reported positive feedback regulation between TERC and the PI3K-AKT pathway that controlled cell proliferation independent of telomerase activity in human fibroblasts. Mechanistically, we revealed that TERC activated the transcription of target genes from the PI3K-AKT pathway, such as PDPK1, by targeting their promoters. Overexpression of PDPK1 partially rescued the deficiency of AKT activation caused by TERC depletion. Furthermore, we found that FOXO1, a transcription factor negatively regulated by the PI3K-AKT pathway, bound to TERC promoter and suppressed its expression. Intriguingly, TERC-induced activation of the PI3K-AKT pathway also played a critical role in the proliferation of activated CD4⁺ T cells. Collectively, our findings identify a novel function of TERC that regulates the PI3K-AKT pathway via positive feedback to elevate cell proliferation independent of telomerase activity and provide a potential strategy to promote CD4⁺ T cells expansion that is responsible for enhancing adaptive immune reactions to defend against pathogens and tumor cells.

Pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (ntESCs), and induced pluripotent stem cells (iPSCs) have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells. In order to maintain their self-renewal and pluripotency, PSCs need to preserve their telomere length and homeostasis. In recent years, increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process. Telomere-associated proteins are not only required for telomere maintenance in both stem cells, their extra-telomeric functions have also been found to be critical as well. Here, we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication that affects an increasing number of cancer survivors. However, the current treatment options for CIPN are limited. Paclitaxel (PTX) is a widely used chemotherapeutic drug that induces senescence in cancer cells. While previous studies have demonstrated that Sonic hedgehog (Shh) can counteract cellular dysfunction during aging, its role in CIPN remains unknown. Herein, the aim of this study was to investigate whether Shh activation could inhibits neuronal/glial senescence and alleviates CIPN. We treated ND7/23 neuronal cells and RSC96 Schwann cells with two selective Shh activators (purmorphamine [PUR] and smoothened agonist [SAG]) in the presence of PTX. Additionally, we utilized a CIPN mouse model induced by PTX injection. To assess cellular senescence, we performed a senescence-associated β-galactosidase (SA-β-gal) assay, measured reactive oxygen species (ROS) levels, and examined the expression of P16, P21, and γH2AX. To understand the underlying mechanisms, we conducted ubiquitin assays, LC-MS/MS, H&E staining, and assessed protein expression through Western blotting and immunofluorescence staining. In vitro, we observed that Shh activation significantly alleviated the senescence-related decline in multiple functions included SA-β-gal activity, expression of P16 and P21, cell viability, and ROS accumulation in DRG sensory neurons and Schwann cells after PTX exposure. Furthermore, our in vivo experiments demonstrated that Shh activation significantly reduced axonal degeneration, demyelination, and improved nerve conduction. Mechanistically, we discovered that PTX reduced the protein level of SP1, which was ubiquitinated by the E3 ligase TRIM25 at the lysine 694 (K694), leading to increased CXCL13 expression, and we found that Shh activation inhibited PTX-induced neuronal/glial senescence and CIPN through the TRIM25-SP1-CXCL13 axis. These findings provide evidence for the role of PTX-induced senescence in DRG sensory neurons and Schwann cells, suggesting that Shh could be a potential therapeutic target for CIPN.

Ferroptosis is involved in various tissue injuries including neurodegeneration, ischemia-reperfusion injury, and acute liver injury. Ferroptosis inhibitors exhibit promising clinical potential in the treatment of various diseases. As a traditional chemical, silymarin has been widely used in healthcare and clinical applications to treat liver injuries in which ferroptosis is involved. Silibinin is the main active ingredient of silymarin. However, the effect of silibinin on ferroptosis and ferroptosis-related diseases remains unclear. Here, we found that silibinin inhibited death in different kinds of cells caused by ferroptosis inducers including RSL3 and erastin. Moreover, silibinin alleviated lipid peroxidation induced by RSL3 without affecting the labile iron pool. Next, the antioxidant activity of silibinin was demonstrated by the DPPH assay. In vivo, silibinin strikingly relieved tissue injuries and ferroptosis in the liver and kidney of glutathione peroxidase 4 (GPX4) knockout C57 BL/6J mice. Moreover, silibinin effectively rescued renal ischemia-reperfusion, a well-known ferroptosis-related disease. In conclusion, our study revealed that silibinin effectively inhibits cell ferroptosis and ferroptosis-related tissue injuries, implicating silibinin as a potential chemical to treat ferroptosis-related diseases.