Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective.

Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular-glue-mediated proximity-induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC-driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure-activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.

Report of Citrus tristeza virus in Diaphorina citri (Hemiotera: Liviidae) insects of different sexes, color morphs, and developmental stages.

Diaphorina citri, also known as the Asian citrus psyllid, is the main vector of 'Candidatus Liberibacter asiaticus' (CLas) associated with citrus Huanglongbing. It has been reported that D. citri could also be infected by Citrus tristeza virus (CTV), a virus that has been previously reported to be vectored by certain aphid species. In this study, the CTV and CLas profiles in different organs, color variants, developmental stages, or sexes of D. citri insects were analyzed. Although no significant differences were found between nymphs and adults in CTV titers, we found that the third instar nymph of D. citri was more efficient in CTV and CLas acquisition compared to the fourth and fifth instars and adults. With the instars of D. citri development, the relationship between the acquiring of CTV and CLas by D. citri seemed to follow an inverse trend, with the titer of CLas increased and the titer of CTV decreased. No significant differences were observed between the 2 sexes of D. citri in acquiring either CTV or CLas titers in the field. However, no differences were drawn among the 3 color morph variants for CTV titers. CTV titers in the midguts of adult D. citri were significantly higher than those in the salivary glands. Both CTV-positive incidence and CTV titers in the midguts of adult D. citri increased with increasing exposure periods. This study provides new data to deepen our understanding of the CTV-involved interaction between D. citri and CLas.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

Red Ginseng Improves D-galactose-Induced Premature Ovarian Failure in Mice Based on Network Pharmacology.

In this study, we evaluated the ameliorative effect and molecular mechanism of red ginseng (Panax ginseng C.A. Meyer) extract (RGE) on D-galactose (D-gal)-induced premature ovarian failure (POF) using network pharmacology analysis. Ginsenosides are important active ingredients in ginseng, which also contains some sugar and amino acid derivatives. We aimed to determine the key proteins through which RGE regulates POF. In this work, we retrieved and screened for active ingredients in ginseng and the corresponding POF disease targets in multiple databases. A PPI network of genes was constructed in the STRING database and core targets were screened using topological analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted in R software. Finally, molecular docking was conducted to validate the results. Female ICR mice were used to establish a POF mouse model for in vivo experiments. Serum levels of relevant estrogens were determined using ELISA and expression levels of relevant proteins in ovarian tissues were detected using immunofluorescence and western blot analysis. Network pharmacology analysis predicted that PI3K, Akt, Bax, Bcl-2, p16, and other proteins were highly correlated with POF and RGE. The results clearly showed that RGE could increase estradiol (E2) and lower follicle-stimulating hormone (FSH) levels in D-gal-fed mice. RGE restored the expression levels of related proteins by reducing Nrf2-mediated oxidative stress, PI3K/Akt-mediated apoptosis, and senescence signaling pathways. Overall, RGE has the potential to prevent and treat POF and is likely to be a promising natural protector of the ovaries.

Bak interacts with AKT and is involved in TNFα/CHX-induced apoptosis.

Bak is important for TNFα/CHX-induced neuronal death, but the precise molecular mechanism remains unclear. At the same time, TNFα/CHX concomitantly activates the phosphorylation of the MAPK and PI3K/AKT kinases. This study for the first time clarified the association between the MAPK and AKT under the TNFα/CHX stimulation upon addition of different kinase inhibitors to show whether Bak is associated with the kinase activation. The bioinformatics software HDOCK predicted the interaction between Bak and AKT. The addition of TNFα/CHX was proposed to destroy the complex, such that the dissociated Bak would exert a proapoptosis effect AKT can influence the inhibition of cell apoptosis. There was no cell death upon inducing TNFα/CHX for 3 h. AKT was less obvious with apoptosis but in the Bak knockout cells, the anti-apoptotic effect of AKT was very obvious. This study, therefore, provides the theoretical basis for the molecular mechanism of apoptosis induced by TNFα/CHX, providing a new target and direction for studying drug resistance.

Century-Long Homogenization of Algal Communities Is Accelerated by Nutrient Enrichment and Climate Warming in Lakes and Reservoirs of the North Temperate Zone.

Anthropogenic pressures can threaten lake and reservoir ecosystems, leading to harmful algal blooms that have become globally widespread. However, patterns of phytoplankton diversity change and community assembly over long-term scales remain unknown. Here, we explore biodiversity patterns in eukaryotic algal (EA) and cyanobacterial (CYA) communities over a century by sequencing DNA preserved in the sediment cores of seven lakes and reservoirs in the North Temperate Zone. Comparisons within lakes revealed temporal algal community homogenization in mesotrophic lakes, eutrophic lakes, and reservoirs over the last century but no systematic losses of α-diversity. Temporal homogenization of EA and CYA communities continued into the modern day probably due to time-lags related to historical legacies, even if lakes go through a eutrophication phase followed by a reoligotrophication phase. Further, algal community assembly in lakes and reservoirs was mediated by both deterministic and stochastic processes, while homogeneous selection played a relatively important role in recent decades due to intensified anthropogenic activities and climate warming. Overall, these results expand our understanding of global change effects on algal community diversity and succession in lakes and reservoirs that exhibit different successional trajectories while also providing a baseline framework to assess their potential responses to future environmental change.

Fe3O4@polydopamine nanoparticle-loaded human umbilical cord mesenchymal stem cells improve the cognitive function in Alzheimer's disease mice by promoting hippocampal neurogenesis.

One of the most promising treatments for neurodegenerative diseases is the stem cell therapy; however, there are still some limitations in the treatment of Alzheimer's disease. In this study, superparamagnetic nanoparticles composed of magnetic Fe3O4 and polydopamine shells were used to label human umbilical cord mesenchymal stem cells (hUC-MSCs) in order to increase the targeting of hUC-MSCs. Our data suggested that Fe3O4@PDA labeling increase the efficiency of hUC-MSCs entering the brain. Moreover, the water maze test showed that compared with hUC-MSCs only, Fe3O4@PDA-labeled hUC-MSCs improved the cognitive ability of APP/PS1 transgenic mice more significantly. Other experimental data showed that the expression of essential proteins in the hippocampus, such as Aß, synaptophysin, brain-derived neurotrophic factor, are affected by Fe3O4@PDA coated-hUC-MSCs. The regulation of Fe3O4@PDA coated-hUC-MSCs could improve the memory and cognitive ability of AD mice by excessive generation of neuroprotective factors, which might be considered a viable therapy to treat AD.

Boosting Room Temperature Phosphorescence Performance by Alkyl Modification for Intravital Orthotopic Lung Tumor Imaging.

Pure organic persistent room temperature phosphorescence (RTP) materials have attracted wide attention owing to their great potential in various applications, particularly in bioimaging. However, it is still a challenge to manufacture organic RTP materials possessing quite high efficiency and long lifetime, owing to the high requirements for triplet excitons. In this study, a series of keto derivatives with efficient RTP in crystals are developed through the regulation of molecular aggregation states by simple alkyl groups, resulting in impressive luminescence performance with a longer lifetime and higher efficiency of up to 868 ms and 51.59%, respectively. All the alkyl-substituted derivatives exhibit bright RTP intensities after heavy grinding with a pestle, indicating their robust RTP features, which are suitable for many fields. Encouraged by the excellent RTP performance of these luminogens in the crystalline state, successful orthotopic lung tumor imaging with a high signal-to-background ratio (SBR) of 65 is demonstrated in this study to provide the promise of pure organic RTP materials for disease diagnosis, which hold the advantages of low autofluorescence interference and high signal-to-background ratio.

Design of a High-Sensitivity Dimeric G-Quadruplex/Hemin DNAzyme Biosensor for Norovirus Detection.

G-quadruplexes can bind with hemin to form peroxidase-like DNAzymes that are widely used in the design of biosensors. However, the catalytic activity of G-quadruplex/hemin DNAzyme is relatively low compared with natural peroxidase, which hampers its sensitivity and, thus, its application in the detection of nucleic acids. In this study, we developed a high-sensitivity biosensor targeting norovirus nucleic acids through rationally introducing a dimeric G-quadruplex structure into the DNAzyme. In this strategy, two separate molecular beacons each having a G-quadruplex-forming sequence embedded in the stem structure are brought together through hybridization with a target DNA strand, and thus forms a three-way junction architecture and allows a dimeric G-quadruplex to form, which, upon binding with hemin, has a synergistic enhancement of catalytic activities. This provides a high-sensitivity colorimetric readout by the catalyzing H2O2-mediated oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline -6-sulfonic acid) diammonium salt (ABTS). Up to 10 nM of target DNA can be detected through colorimetric observation with the naked eye using our strategy. Hence, our approach provides a non-amplifying, non-labeling, simple-operating, cost-effective colorimetric biosensing method for target nucleic acids, such as norovirus-conserved sequence detection, and highlights the further implication of higher-order multimerized G-quadruplex structures in the design of high-sensitivity biosensors.

Targeted Enrichment of Enzyme-Instructed Assemblies in Cancer Cell Lysosomes Turns Immunologically Cold Tumors Hot.

Lysosome-relevant cell death induced by lysosomal membrane permeabilization (LMP) has recently attracted increasing attention. However, nearly no studies show that currently available LMP inducers can evoke immunogenic cell death (ICD) or convert immunologically cold tumors to hot. Herein, we report a LMP inducer named TPE-Py-pYK(TPP)pY, which can respond to alkaline phosphatase (ALP), leading to formation of nanoassembies along with fluorescence and singlet oxygen turn-on. TPE-Py-pYK(TPP)pY tends to accumulate in ALP-overexpressed cancer cell lysosomes as well as induce LMP and rupture of lysosomal membranes to massively evoke ICD. Such LMP-induced ICD effectively converts immunologically cold tumors to hot as evidenced by abundant CD8+ and CD4+ T cells infiltration into the cold tumors. Exposure of ALP-catalyzed nanoassemblies in cancer cell lysosomes to light further intensifies the processes of LMP, ICD and cold-to-hot tumor conversion. This work thus builds a new bridge between lysosome-relevant cell death and cancer immunotherapy.

Boosting Photoacoustic Effect via Intramolecular Motions Amplifying Thermal-to-Acoustic Conversion Efficiency for Adaptive Image-Guided Cancer Surgery.

Photoacoustic (PA) imaging emerges as a promising technique for biomedical applications. The development of new strategies to boost PA conversion without depressing other properties (e.g., fluorescence) is highly desirable for multifunctional imaging but difficult to realize. Here, we report a new phenomenon that active intramolecular motions could promote PA signal by specifically increasing thermal-to-acoustic conversion efficiency. The compound with intense intramolecular motion exhibits amplified PA signal by elevating thermal-to-acoustic conversion, and the fluorescence also increases due to aggregation-induced emission signature. The simultaneously high PA and fluorescence brightness of TPA-TQ3 NPs enable precise image-guided surgery. The preoperative fluorescence and PA imaging are capable of locating orthotopic breast tumor in a high-contrast manner, and the intraoperative fluorescence imaging delineates tiny residual tumors. This study highlights a new design guideline of intramolecular motion amplifying PA effect.

Apparent relationships between anthropogenic factors and climate change indicators and POPs deposition in a lacustrine system.

Climate change and anthropogenic activities are expected to impact the environmental behaviors and fates of persistent organic pollutants (POPs), however, quantitative studies on these combined factors are scarce. In this study, dichlorodiphenyltrichloroethane (DDTs), polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs) were used as examples to identify how and when those factors may be related to the deposition of POPs in the sediment of Lake Chaohu, China, using generalized additive models (GAMs). Three historical trends of DDT, PAH, and PCB deposition were delineated in a dated sediment core encompassing ~100 years of historical record: a steady state or gradually increasing stage, a rapidly increasing stage, and a declining stage. The GAM results showed that aquatic total phosphorus (TP) concentrations and regional GDP (anthropogenic factors) were dominant contributors to POP accumulation rates in the lake sediment. The fitted relationships between air temperature and sedimentary DDT and PAH concentrations were linear and negative, while a positive linear relationship was found for PCBs, suggesting that Lake Chaohu may have become a net source for DDTs and PAHs, and a sink for PCBs, under a progressively warming climate.

Source apportionment of perfluoroalkyl substances in surface sediments from lakes in Jiangsu Province, China: Comparison of three receptor models.

Receptor models have been proved as useful tools to identify source categories and quantitatively calculate the contributions of extracted sources. In this study, sixty surface sediment samples were collected from fourteen lakes in Jiangsu Province, China. The total concentrations of C4-C14-perfluoroalkyl carboxylic acids and perfluorooctane sulfonic acid (∑12PFASs) in sediments ranged from 0.264 to 4.44ng/gdw (dry weight), with an average of 1.76ng/gdw. Three commonly-applied receptor models, namely principal component analysis-multiple linear regression (PCA-MLR), positive matrix factorization (PMF) and Unmix models, were employed to apportion PFAS sources in sediments. Overall, these three models all could well track the ∑12PFASs concentrations as well as the concentrations explained in sediments. These three models identified consistently four PFAS sources: the textile treatment sources, the fluoropolymer processing aid/fluororesin coating sources, the textile treatment/metal plating sources and the precious metal sources, contributing 28.1%, 37.0%, 29.7% and 5.3% by PCA-MLR model, 30.60%, 39.3%, 22.4% and 7.7% by PMF model, and 20.6%, 52.4%, 20.2% and 6.8% by Unmix model to the ∑12PFASs, respectively. Comparative statistics of multiple analytical methods could minimize individual-method weaknesses and provide convergent results to enhance the persuasiveness of the conclusions. The findings could give us a better knowledge of PFAS sources in aquatic environments.

Algal uptake of dissolved organic nitrogen in wastewater treatment plants.

The algal uptake of dissolved organic nitrogen (DON) in the anaerobic-anoxic-oxic (A2O) process was investigated in this study. Anaerobic, aerobic and effluent DON samples from two wastewater treatment plants (WWTPs) were separated into hydrophilic and hydrophobic fractions using a DAX-8 resin coupled with an anion exchange resin and a nanofiltration (NF) pretreatment. Hydrophilic DON accounted for 66.66%-88.74% of the entire DON for the two plants evaluated. After a 15-day incubation, 16.95%-91.75% DON was bioavailable for algal growth, and untreated samples exhibited higher DON bioavailability, with 52.83% DON average uptake rates, compared with the hydrophilic and hydrophobic fractions (45.53% and 44.40%, respectively) because the pretreatment caused the inorganic salt to be resistant to algae. Anaerobic untreated samples, hydrophilic fractions and hydrophobic fractions showed higher DON reduction rates and higher biomass accumulation compared with the other DON fractions due to the decomposition of resistant organics by anaerobic and anoxic bacteria. DON in aerobic and effluent samples of plant A was more bioavailable than that of plant B with usages of 27.49%-55.26% DON. DON bioavailability in the anaerobic-anoxic-oxic process decreased in the following order: anaerobic>effluent>aerobic. The DON contents were reduced after anaerobic treatment in the two plants. The EEM-PARAFAC model identified three DON components, including two humic acid-like substances and one protein-like substance in plant A and two protein-like substances and one humic acid-like substance in plant B.

Microbial bioavailability of dissolved organic nitrogen (DON) in the sediments of Lake Shankou, Northeastern China.

Dissolved organic nitrogen (DON) extracted from Lake Shankou sediments using KCl was isolated into hydrophobic and hydrophilic fractions. The bioavailabilities of the hydrophobic and hydrophilic fractions to three types of bacterial communities collected from sediments, activated sludge and compost products were examined. The DON recoveries obtained by DAX-8 and cation exchange resins treatment were 96.17%±1.58% and 98.14%±0% for the samples obtained from N4 and N14 stations, respectively. After 25 days of incubation at 25°C, most DON (59% to 96%) was degraded. Hydrophilic DON exhibited a higher reduction rate than hydrophobic DON during the growth phase. Untreated wastewater from Changshuihe town was the main degradable DON source to station N4, and 93% of hydrophilic DON and 80% of hydrophobic DON were degraded. Station N14 received a large amount of refractory DON from forest soils and exhibited DON degradation rates of 82% and 71% for the hydrophilic and hydrophobic fractions, respectively. Amino acid contents and fluorescence intensities were also analyzed. Approximately 27% to 74% of amino acids were taken up by day 5, and their concentration gradually increased in the following days due to the decomposition of dissolved proteins. Parallel factor analysis resulted in identification of tryptophan-like proteins, tyrosine-like proteins and FA-like substances. During the growth phase, 40%-51% of the tryptophan-like proteins were taken up by bacteria, and the accumulation of tyrosine-like proteins was attributed to the release of biotic substances. The concentration of the FA-like substances decreased due to microbial decomposition.

Mobility and sulfidization of heavy metals in sediments of a shallow eutrophic lake, Lake Taihu, China.

The technique of DGT (diffusive gradients in thin films) using three diffusive gel thicknesses was applied to estimate the mobility and bioavailability of heavy metals in sediments and porewater of Lake Taihu, China. The DGT results showed significantly positive correlations between Co, Pb, Cd and Mn, and Ni and Fe concentrations in porewater. Cu and Zn showed a significantly negative correlation with Mn, due to Cu combination with carbonates and Zn derived from agricultural pollution, respectively. The rank order of average concentrations of Co, Ni and Cd at each station was DGT1.92>DGT0.78>DGT0.39, suggesting stronger resupply from sediments to porewater when using thicker diffusive gels. Comparing centrifugation and DGT measurements, Co, Ni and Cd are highly labile; Mn and Fe are moderately labile; and Cu, Zn and Pb are slightly labile. The variations of AVS concentrations in sediment cores indicate that metal sulfides in deeper layers are easily diffused into surface sediments.

Arsenic fractionation and contamination assessment in sediments of thirteen lakes from the East Plain and Yungui Plateau Ecoregions, China.

Arsenic (As) fractions in the sediments of seven lakes from East Plain Ecoregion and six lakes from Yungui Plateau Ecoregion, China, were investigated. Results indicated that the total As concentrations in sediment samples of lakes of the East Plain Lake Ecoregion are higher than those of Yungui Plateau Lake Ecoregion. Residual As is the main fraction in sediment samples of lakes from both ecoregions, followed by reducible As and soluble or oxidizable As. The total As is correlated to oxidizable As and residual As in sediment samples from both lake ecoregions. As distribution in sediment samples of lakes of the East Plain Ecoregion appears to be affected by human activity, while the As origin mainly comes from natural sources in sediment samples of lakes in the Yungui Plateau Ecoregion. The potential ecological risk index and geoaccumulation index values suggest "low to moderate" risk degree and "unpolluted to moderately polluted" for As in the studied lake sediments.

Inactivation of harmful cyanobacteria Microcystis aeruginosa by Cu2+ doped corn stalk biochar treated with different pyrolysis temperatures.

In this study, biochars (BCs) derived from corn stalk treated at various pyrolysis temperatures (350-950 °C) were prepared and then loaded with Cu2+ to form highly efficient algaecide, i.e. Cu2+-doped BC composites (Cu-BCs). The results showed BCs pyrolyzed at higher temperatures suppressed the growth of Microcystis aeruginosa in the order of BC550 ≫ BC750 > BC950, while BC350 accelerated cell growth due to the release of inorganic nutrients. The difference could be attributed to the physicochemical characteristics, including specific surface area, adsorption capacity of nutrients and the presence of particularly persistent free radicals. Furthermore, Cu-BCs exhibited the improved inactivation performance, but the 72 h growth inhibition rates and reaction activities of Cu-BCs were still influenced by the Cu2+ loading ratio and pyrolysis temperature. These results, reported for the first time, demonstrated the algae inactivation efficiency of pristine BCs, and Cu-BCs were principally manipulated by the biochar pyrolysis temperature.

Effects of environmental microplastic exposure on Chlorella sp. biofilm characteristics and its interaction with nitric oxide signaling.

Microalgal biofilm is promising in simultaneous pollutants removal, CO2 fixation, and biomass resource transformation when wastewater is used as culturing medium. Nitric oxide (NO) often accumulates in microalgal cells under wastewater treatment relevant abiotic stresses such as nitrogen deficiency, heavy metals, and antibiotics. However, the influence of emerging contaminants such as microplastics (MPs) on microalgal intracellular NO is still unknown. Moreover, the investigated MPs concentrations among existing studies were mostly several magnitudes higher than in real wastewaters, which could offer limited guidance for the effects of MPs on microalgae at environment-relevant concentrations. Therefore, this study investigated three commonly observed MPs in wastewater at environment-relevant concentrations (10-10,000 µg/L) and explored their impacts on attached Chlorella sp. growth characteristics, nutrients removal, and anti-oxidative responses (including intracellular NO content). The nitrogen source NO3--N at 49 mg/L being 20 % of the nitrogen strength in classic BG-11 medium was selected for MPs exposure experiments because of least intracellular NO accumulation, so that disturbance of intracellular NO by nitrogen availability could be avoided. Under such condition, 10 µg/L polyethylene (PE) MPs displayed most significant microalgal growth inhibition comparing with polyvinyl chloride (PVC) and polyamide (PA) MPs, showing extraordinarily low chlorophyll a/b ratios, and highest superoxide dismutase (SOD) activity and intracellular NO content after 12 days of MPs exposure. PVC MPs exposed cultures displayed highest malonaldehyde (MDA) content because of the toxic characteristics of organochlorines, and most significant correlations of intracellular NO content with conventional anti-oxidative parameters of SOD, CAT (catalase), and MDA. MPs accelerated phosphorus removal, and the type rather than concentration of MPs displayed higher influences, following the trend of PE > PA > PVC. This study expanded the knowledge of microalgal biofilm under environment-relevant concentrations of MPs, and innovatively discovered the significance of intracellular NO as a more sensitive indicator than conventional anti-oxidative parameters under MPs exposure.

Drought limits vegetation carbon sequestration by affecting photosynthetic capacity of semi-arid ecosystems on the Loess Plateau.

Drought is the driver for ecosystem production in semi-arid areas. However, the response mechanism of ecosystem productivity to drought remains largely unknown. In particular, it is still unclear whether drought limits the production via photosynthetic capacity or phenological process. Herein, we assess the effects of maximum seasonal photosynthesis, growing season length, and climate on the annual gross primary productivity (GPP) in vegetation areas of the Loess Plateau using multi-source remote sensing and climate data from 2001 to 2021. We found that maximum seasonal photosynthesis rather than growing season length dominates annual GPP, with above 90 % of the study area showing significant and positive correlation. GPP and maximum seasonal photosynthesis were positively correlated with self-calibrating Palmer Drought Severity Index (scPDSI), standardized precipitation and evapotranspiration index (SPEI) in >95 % of the study area. Structural equation model demonstrated that both drought indices contributed to the annual GPP by promoting the maximum seasonal photosynthesis. Total annual precipitation had a positive and significant effect on two drought indices, whereas the effects of temperature and radiation were not significant. Evidence from wood formation data also confirmed that low precipitation inhibited long-term carbon sequestration by decreasing the maximum growth rate in forests. Our findings suggest that drought limits ecosystem carbon sequestration by inhibiting vegetation photosynthetic capacity rather than phenology, providing a support for assessing the future dynamics of the terrestrial carbon cycle and guiding landscape management in semi-arid ecosystems.