Snapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism.

Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via Gi and ß-arrestin signaling pathways. However, the lack of understanding of the mechanism of ß-arrestin-1 (ßarr1) coupling and signaling bias has hindered drug development targeting CB1. Here, we present the high-resolution cryo-electron microscopy structure of CB1-ßarr1 complex bound to the synthetic cannabinoid MDMB-Fubinaca (FUB), revealing notable differences in the transducer pocket and ligand-binding site compared with the Gi protein complex. ßarr1 occupies a wider transducer pocket promoting substantial outward movement of the TM6 and distinctive twin toggle switch rearrangements, whereas FUB adopts a different pose, inserting more deeply than the Gi-coupled state, suggesting the allosteric correlation between the orthosteric binding pocket and the partner protein site. Taken together, our findings unravel the molecular mechanism of signaling bias toward CB1, facilitating the development of CB1 agonists.

Targeting thalamic circuits rescues motor and mood deficits in PD mice.

Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Benchmarking mapping algorithms for cell-type annotating in mouse brain by integrating single-nucleus RNA-seq and Stereo-seq data.

Limited gene capture efficiency and spot size of spatial transcriptome (ST) data pose significant challenges in cell-type characterization. The heterogeneity and complexity of cell composition in the mammalian brain make it more challenging to accurately annotate ST data from brain. Many algorithms attempt to characterize subtypes of neuron by integrating ST data with single-nucleus RNA sequencing (snRNA-seq) or single-cell RNA sequencing. However, assessing the accuracy of these algorithms on Stereo-seq ST data remains unresolved. Here, we benchmarked 9 mapping algorithms using 10 ST datasets from four mouse brain regions in two different resolutions and 24 pseudo-ST datasets from snRNA-seq. Both actual ST data and pseudo-ST data were mapped using snRNA-seq datasets from the corresponding brain regions as reference data. After comparing the performance across different areas and resolutions of the mouse brain, we have reached the conclusion that both robust cell-type decomposition and SpatialDWLS demonstrated superior robustness and accuracy in cell-type annotation. Testing with publicly available snRNA-seq data from another sequencing platform in the cortex region further validated our conclusions. Altogether, we developed a workflow for assessing suitability of mapping algorithm that fits for ST datasets, which can improve the efficiency and accuracy of spatial data annotation.

MdMYB44-like positively regulates salt and drought tolerance via the MdPYL8-MdPP2CA module in apple.

Abscisic acid (ABA) is involved in salt and drought stress responses, but the underlying molecular mechanism remains unclear. Here, we demonstrated that the overexpression of MdMYB44-like, an R2R3-MYB transcription factor, significantly increases the salt and drought tolerance of transgenic apples and Arabidopsis. MdMYB44-like inhibits the transcription of MdPP2CA, which encodes a type 2C protein phosphatase that acts as a negative regulator in the ABA response, thereby enhancing ABA signaling-mediated salt and drought tolerance. Furthermore, we found that MdMYB44-like and MdPYL8, an ABA receptor, form a protein complex that further enhances the transcriptional inhibition of the MdPP2CA promoter by MdMYB44-like. Significantly, we discovered that MdPP2CA can interfere with the physical association between MdMYB44-like and MdPYL8 in the presence of ABA, partially blocking the inhibitory effect of the MdMYB44-like-MdPYL8 complex on the MdPP2CA promoter. Thus, MdMYB44-like, MdPYL8, and MdPP2CA form a regulatory loop that tightly modulates ABA signaling homeostasis under salt and drought stress. Our data reveal that MdMYB44-like precisely modulates ABA-mediated salt and drought tolerance in apples through the MdPYL8-MdPP2CA module.

Disrupted Binding of Cystathionine γ-Lyase to p53 Promotes Endothelial Senescence.

BACKGROUND: Advanced age is unequivocally linked to the development of cardiovascular disease; however, the mechanisms resulting in reduced endothelial cell regeneration remain poorly understood. Here, we investigated novel mechanisms involved in endothelial cell senescence that impact endothelial cell transcription and vascular repair after injury. METHODS: Native endothelial cells were isolated from young (20±3.4 years) and aged (80±2.3 years) individuals and subjected to molecular analyses to assess global transcriptional and metabolic changes. In vitro studies were conducted using primary human and murine endothelial cells. A murine aortic re-endothelialization model was used to examine endothelial cell regenerative capacity in vivo. RESULTS: RNA sequencing of native endothelial cells revealed that aging resulted in p53-mediated reprogramming to express senescence-associated genes and suppress glycolysis. Reduced glucose uptake and ATP contributed to attenuated assembly of the telomerase complex, which was required for endothelial cell proliferation. Enhanced p53 activity in aging was linked to its acetylation on K120 due to enhanced activity of the acetyltransferase MOZ (monocytic leukemic zinc finger). Mechanistically, p53 acetylation and translocation were, at least partially, attributed to the loss of the vasoprotective enzyme, CSE (cystathionine γ-lyase). CSE physically anchored p53 in the cytosol to prevent its nuclear translocation and CSE absence inhibited AKT (Protein kinase B)-mediated MOZ phosphorylation, which in turn increased MOZ activity and subsequently p53 acetylation. In mice, the endothelial cell-specific deletion of CSE activated p53, induced premature endothelial senescence, and arrested vascular repair after injury. In contrast, the adeno-associated virus 9-mediated re-expression of an active CSE mutant retained p53 in the cytosol, maintained endothelial glucose metabolism and proliferation, and prevented endothelial cell senescence. Adenoviral overexpression of CSE in native endothelial cells from aged individuals maintained low p53 activity and reactivated telomerase to revert endothelial cell senescence. CONCLUSIONS: Aging-associated impairment of vascular repair is partly determined by the vasoprotective enzyme CSE.

Excessive apoptosis of Rip1-deficient T cells leads to premature aging.

In mammals, the most remarkable T cell variations with aging are the shrinking of the naïve T cell pool and the enlargement of the memory T cell pool, which are partially caused by thymic involution. However, the mechanism underlying the relationship between T-cell changes and aging remains unclear. In this study, we find that T-cell-specific Rip1 KO mice show similar age-related T cell changes and exhibit signs of accelerated aging-like phenotypes, including inflammation, multiple age-related diseases, and a shorter lifespan. Mechanistically, Rip1-deficient T cells undergo excessive apoptosis and promote chronic inflammation. Consistent with this, blocking apoptosis by co-deletion of Fadd in Rip1-deficient T cells significantly rescues lymphopenia, the imbalance between naïve and memory T cells, and aging-like phenotypes, and prolongs life span in T-cell-specific Rip1 KO mice. These results suggest that the reduction and hyperactivation of T cells can have a significant impact on organismal health and lifespan, underscoring the importance of maintaining T cell homeostasis for healthy aging and prevention or treatment of age-related diseases.

The Fused/Smurf complex controls the fate of Drosophila germline stem cells by generating a gradient BMP response.

In the Drosophila ovary, germline stem cells (GSCs) are maintained primarily by bone morphogenetic protein (BMP) ligands produced by the stromal cells of the niche. This signaling represses GSC differentiation by blocking the transcription of the differentiation factor Bam. Remarkably, bam transcription begins only one cell diameter away from the GSC in the daughter cystoblasts (CBs). How this steep gradient of response to BMP signaling is formed has been unclear. Here, we show that Fused (Fu), a serine/threonine kinase that regulates Hedgehog, functions in concert with the E3 ligase Smurf to regulate ubiquitination and proteolysis of the BMP receptor Thickveins in CBs. This regulation generates a steep gradient of BMP activity between GSCs and CBs, allowing for bam expression on CBs and concomitant differentiation. We observed similar roles for Fu during embryonic development in zebrafish and in human cell culture, implying broad conservation of this mechanism.

APC mutations disrupt ß-catenin destruction complex condensates organized by Axin phase separation.

The Wnt/ß-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the ß-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of ß-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the ß-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3ß and CK1α were unsuccessfully recruited, preventing ß-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of ß-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.

InCl3-Assisted Surface Defects Restoring to Enhance Lead-Free Cs2ZrCl6 Nanocrystals for X-Ray Imaging and Blue LED Applications.

As one type of recent emerging lead-free perovskites, Cs2ZrCl6 nanocrystals are widely concerned, benefiting from the eminent designability, high X-ray cutoff efficiency, and favorable stability. Improving the luminescence performance of Cs2ZrCl6 nanocrystals has great importance to cater for practical applications. In view of the surface defects frequently formed by the liquid phase method, the particle morphology and surface quality of this material are expected to be regulated if certain intervention is made in the synthesis process. In the work, differing from normal cell lattice modulation based on the ion doping, the grain size and surface morphology of Cs2ZrCl6 nanocrystals are optimized via adding a certain amount of InCl3 to the synthetic solution. The surface defects are restored to inhibit the defect-induced non-radiative transition, resulting in the improvement of the luminescence properties. Moreover, a flexible Cs2ZrCl6@polydimethylsiloxane film with excellent heat, water, and bending resistance and a light-emitting diode (LED) device are fabricated, exhibiting excellent application potential for X-ray imaging and blue LED.

Highly Efficient Oral Iguratimod/Polyvinyl Alcohol Nanodrugs Fabricated by High-Gravity Nanoprecipitation Technique for Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA), a systemic autoimmune disease, poses a significant human health threat. Iguratimod (IGUR), a novel disease-modifying antirheumatic drug (DMARD), has attracted great attention for RA treatment. Due to IGUR's hydrophobic nature, there's a pressing need for effective pharmaceutical formulations to enhance bioavailability and therapeutic efficacy. The high-gravity nanoprecipitation technique (HGNPT) emerges as a promising approach for formulating poorly water-soluble drugs. In this study, IGUR nanodrugs (NanoIGUR) are synthesized using HGNPT, with a focus on optimizing various operational parameters. The outcomes revealed that HGNPT enabled the continuous production of NanoIGUR with smaller sizes (ranging from 300 to 1000 nm), more uniform shapes, and reduced crystallinity. In vitro drug release tests demonstrated improved dissolution rates with decreasing particle size and crystallinity. Notably, in vitro and in vivo investigations showcased NanoIGUR's efficacy in inhibiting synovial fibroblast proliferation, migration, and invasion, as well as reducing inflammation in collagen-induced arthritis. This study introduces a promising strategy to enhance and broaden the application of poorly water-soluble drugs.

Platelet-Derived Growth Factor Nanocapsules with Tunable Controlled Release for Chronic Wound Healing.

Chronic wounds have emerged as an increasingly critical clinical challenge over the past few decades, due to their increasing incidence and socioeconomic burdens. Platelet-derived growth factor (PDGF) plays a pivotal role in regulating processes such as fibroblast migration, proliferation, and vascular formation during the wound healing process. The delivery of PDGF offers great potential for expediting the healing of chronic wounds. However, the clinical effectiveness of PDGF in chronic wound healing is significantly hampered by its inability to maintain a stable concentration at the wound site over an extended period. In this study, a controlled PDGF delivery system based on nanocapsules is proposed. In this system, PDGF is encapsulated within a degradable polymer shell. The release rate of PDGF from these nanocapsules can be precisely adjusted by controlling the ratios of two crosslinkers with different degradation rates within the shells. As demonstrated in a diabetic wound model, improved therapeutic outcomes with PDGF nanocapsules (nPDGF) treatment are observed. This research introduces a novel PDGF delivery platform that holds promise for enhancing the effectiveness of chronic wound healing.

A novel miR160a-GmARF16-GmMYC2 module determines soybean salt tolerance and adaptation.

Salt stress is a major challenge that has a negative impact on soybean growth and productivity. Therefore, it is important to understand the regulatory mechanism of salt response to ensure soybean yield under such conditions. In this study, we identified and characterized a miR160a-GmARF16-GmMYC2 module and its regulation during the salt-stress response in soybean. miR160a promotes salt tolerance by cleaving GmARF16 transcripts, members of the Auxin Response Factor (ARF) family, which negatively regulates salt tolerance. In turn, GmARF16 activates GmMYC2, encoding a bHLH transcription factor that reduces salinity tolerance by down-regulating proline biosynthesis. Genomic analysis among wild and cultivated soybean accessions identified four distinct GmARF16 haplotypes. Among them, the GmARF16H3 haplotype is preferentially enriched in localities with relatively saline soils, suggesting GmARF16H3 was artificially selected to improve salt tolerance. Our findings therefore provide insights into the molecular mechanisms underlying salt response in soybean and provide valuable genetic targets for the molecular breeding of salt tolerance.

EDS1-interacting J protein 1 is an essential negative regulator of plant innate immunity in Arabidopsis.

Plants have evolved precise mechanisms to optimize immune responses against pathogens. ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) plays a vital role in plant innate immunity by regulating basal resistance and effector-triggered immunity. Nucleocytoplasmic trafficking of EDS1 is required for resistance reinforcement, but the molecular mechanism remains elusive. Here, we show that EDS1-INTERACTING J PROTEIN1 (EIJ1), which acts as a DnaJ protein-like chaperone in response to pathogen infection, functions as an essential negative regulator of plant immunity by interacting with EDS1. The loss-of-function mutation of EIJ1 did not affect plant growth but significantly enhanced pathogen resistance. Upon pathogen infection, EIJ1 relocalized from the chloroplast to the cytoplasm, where it interacted with EDS1, thereby restricting pathogen-triggered trafficking of EDS1 to the nucleus and compromising resistance at an early infection stage. During disease development, EIJ1 was gradually degraded, allowing the nuclear accumulation of EDS1 for transcriptional resistance reinforcement. The avirulent strain Pst DC3000 (AvrRps4) abolished the repressive action of EIJ1 by rapidly inducing its degradation in the effector-triggered immunity response. Thus, our findings show that EIJ1 is an essential EDS1-dependent negative regulator of innate plant immunity and provide a mechanistic understanding of how the nuclear versus cytoplasmic distribution of EDS1 is regulated during the immune response.

Expression of a single-chain monellin (MNEI) mutant with enhanced stability in transgenic mice milk.

Monellin is a sweet protein that may be used as a safe and healthy sweetener. However, due to its low stability, the application of monellin is currently very limited. Here, we describe a wild-type, a double-sites mutant (E2N/E23A) and a triple-sites mutant (N14A/E23Q/S76Y) of single-chain monellin (MNEI) expressed in transgenic mice milk. Based on enzyme-linked immunoassay (ELISA), Western blot, and sweetness intensity testing, their sweetness and stability were compared. After boiling for 2 min at different pH conditions (2.5, 5.1, 6.8, and 8.2), N14A/E23Q/S76Y-MNEI showed significantly higher sweetness and stability than the wild-type and E2N/E23A-MNEI. These results suggest that N14A/E23Q/S76Y-MNEI shows remarkable potential as a sweetener in the future.

The mechanism of lncRNA SNHG1 in osteogenic differentiation via miR-497-5p/ HIF1AN axis.

The pivotal role of lncRNAs in osteoporosis progression and development necessitates a comprehensive exploration of the functional and precise molecular mechanisms underlying lncRNA SNHG1's regulation of osteoblast differentiation and calcification. The study involved inducing BMSCs cells to differentiate into osteoblasts, followed by transfections of miR-497-5p inhibitors, pcDNA3.1-SNHG1, sh-HIF1AN, miR-497-5p mimics, and respective negative controls into BMSCs. Quantitative PCR (qPCR) was employed to assess the expression of SNHG1 and miR-497-5p. Western Blotting was conducted to measure the levels of short stature-related transcription factor 2 (RUNX2), osteopontin (OPN), osteocalcin (OCN), and HIF1AN. Alkaline phosphatase (ALP) activity was determined using appropriate assay kits. Calcium nodule staining was performed through Alizarin red staining. Dual luciferase reporter gene assays were executed to validate the interaction between SNHG1 and miR-497-5p, as well as HIF1AN. Throughout osteogenic differentiation, there was a down-regulation of SNHG1 and HIF1AN, in contrast to an elevation in miR-497-5p levels. Direct interactions between miR-497-5p and both SNHG1 and HIF1AN were observed. Notably, SNHG1 exhibited the ability to modulate HIF1AN by influencing miR-497-5p, thereby inhibiting osteogenic differentiation. Functioning as a competitive endogenous RNA, lncRNA SNHG1 exerts an inhibitory influence on osteogenic differentiation via the miR-497-5p/HIF1AN axis. This highlights the potential for lncRNA SNHG1 to emerge as a promising therapeutic target for osteoporosis. The study's findings pave the way for a novel target strategy in the future treatment of osteoporosis.

Psychological Mechanisms of Internalized HIV Stigma Affect Sleep Impairment among People Living with HIV in China: A follow-up Study.

Prior studies have demonstrated that HIV-related stigma (e.g., internalized HIV stigma) is detrimental to the physical and mental health (e.g., sleep impairment and depressive symptoms) of people living with HIV (PLWH). However, follow-up data are limited regarding the longitudinal relationships between internalized HIV stigma, future orientation, self-esteem, depressive symptoms, and sleep impairment. The present study attempted to examine a mediation model involving these variables among Chinese PLWH. A two-wave follow-up design (6 months intervals) was employed in a final sample of 1,140 Chinese PLWH (Mage = 41.63, SD = 9.29, age range: 21-67 years; 64.6% men). Participants completed Internalized HIV Stigma Scale, Optimism About the Future Scale, Rosenberg Self-Esteem Scale, Center of Epidemiological Studies Depression Scale, and an adapted version of Pittsburgh Sleep Quality Index. Results revealed that internalized HIV stigma at baseline had a significant direct relationship with sleep impairment over time, and a significant indirect relationship with increased sleep impairment over time via future orientation and depressive symptoms. Furthermore, the linkage between internalized HIV stigma and sleep impairment was serially mediated via self-esteem and depressive symptoms. This study highlights the deleterious effects of internalized HIV stigma on the physical and psychological health of PLWH. The findings suggest that interventions targeting internalized HIV stigma and related factors such as future orientation, self-esteem, and depressive symptoms may facilitate improvements in sleep quality and overall well-being among PLWH.

Longitudinal Analysis of the Relationship Between Internalized HIV Stigma, Perceived Social Support, Resilience, and Depressive Symptoms Among People Living with HIV in China: A Four-Wave Model.

Depression is one of the most common mental health problems among people living with HIV (PLWH). However, the longitudinal psychological mechanism underlying the link of internalized HIV stigma and depressive symptoms remains a research gap. This study attempted to articulate how and to what extent perceived social support and resilience mediate the longitudinal associations between internalized HIV stigma and depressive symptoms. A sample consisting of 1,098 Chinese PLWH (Mage = 38.63, SD = 9.20; 63.9% male) with a six-month interval and four waves of follow-up was used in the current study. Participants were asked to complete self-report questionnaires. The associations among main study variables were examined via a complete longitudinal mediation approach. Results indicated that the linkage between internalized HIV stigma at T1 and depressive symptoms at T4 was serially mediated by perceived social support at T2 and resilience at T3, and perceived social support at T2 and depressive symptoms at T3 serially mediated the relationship between resilience at T1 and internalized HIV stigma at T4. Depressive symptoms at a previous time point consistently predicted the levels of internalized HIV stigma at subsequent time points. The study highlights the complex interplay between internalized HIV stigma, mental health problems, and protective factors in a longitudinal context. The findings suggest the need to incorporate interventions aimed at enhancing social support and resilience in mental health programs for PLWH, as these factors may interrupt the pathway from internalized HIV stigma to depressive symptoms and potentially improve the overall psychological well-being of this population.

Psychosocial Factors Predicting HIV Disclosure Stage Transitions: An Evaluation of A Theory-Based Parental HIV Disclosure Intervention among Parents Living with HIV in China.

Appropriate parental HIV disclosures (i.e., parents living with HIV [PLH] tell their HIV diagnosis to their children) benefit parents, children, and family relations. Psychosocial factors could influence the decision-making process of parental HIV disclosure. Using the Health Action Process Approach to frame stages (pre-intention, intention, and action) in the decision-making process, this study aimed to investigate how psychosocial factors predict HIV disclosure stage transitions among PLH in China. Data were collected from a randomized clinical trial of a theory-based parental HIV disclosure intervention among 791 PLH. The predictive effects of psychosocial factors on disclosure stage transitions were examined using a Markov chain model matrix. Results showed that action self-efficacy and action planning were significant predictors of parental HIV disclosure stage transitions. Considering stage-specific psychosocial predictors may contribute to effective interventions to promote appropriate HIV disclosure among PLH in China.

Exploring the Longitudinal Influence of Perceived Social Support, HIV Stigma, and Future Orientation on Depressive Symptoms Among People Living with HIV in China.

Prior studies demonstrated that perceived social support is negatively associated with behavioral and mental health problems among people living with HIV (PLWH). However, longitudinal data regarding the associations between perceived social support, internalized HIV stigma, future orientation, and depressive symptoms are limited. The current study aimed to investigate the possible indirect relationship between these variables using four-wave follow-up data (6-month intervals) from a sample of 1,098 Chinese PLWH (Mage = 38.63, SD = 9.20, age range: 18-60 years; 63.9% men). All participants were asked to complete an adapted version of Perceived Social Support Scale, Internalized HIV Stigma Scale, Optimism About the Future Scale, and Center of Epidemiological Studies Depression Scale. Results indicated that perceived social support at baseline was negatively related to depressive symptoms at wave 4. Internalized HIV stigma at wave 2 and future orientation at wave 3 indirectly affected the linkage between perceived social support at baseline and depressive symptoms serially over time. This study highlights the essential role of perceived social support in alleviating depressive symptoms among PLWH, and underscores the complex interplay in which internalized HIV stigma and future orientation serially mediated the relationship between perceived social support and depressive symptoms. These findings suggest the need for integrated interventions to enhance social support, address HIV-related stigma, and promote positive future orientation, which could potentially alleviate depressive symptoms and promote mental well-being among PLWH.

How Does Anticipated HIV Stigma Affect Medication Adherence? A Longitudinal Path Analysis Model.

Prior research has documented that anticipated HIV stigma may play an important predictive role in medication adherence among people living with HIV (PLWH). However, longitudinal data on the mechanisms underlying this linkage are scarce. The current study aimed to explore the longitudinal mediation association among anticipated HIV stigma, medication adherence support, HIV self-management, and medication adherence. A four-wave sample consisting of 1,098 Chinese PLWH (Mage = 38.63, SD = 9.20; 63.9% male) with a six-month interval was used in the current study. Participants were asked to complete self-report questionnaires. A path analysis model was analyzed. Results indicate that anticipated HIV stigma at baseline was positively related to medication adherence at Time 4 (T4). Medication adherence support at Time 2 (T2) and HIV self-management at Time 3 (T3) serially mediated the anticipated HIV stigma at Time 1 (T1) and medication adherence at T4. These findings provide critical insights into the mediating roles of medication adherence support and HIV self-management in the relationship between anticipated HIV stigma and medication adherence over time. Such an understanding has important implications for the development of tailored interventions and public health strategies aimed at improving medication adherence among PLWH in the context of HIV-related stigma.