Transglutaminases (TGs) are calcium-dependent enzymes that cross-link proteins, contributing to apoptosis, extracellular matrix (ECM) stabilization, and inflammation. While TG2 has been extensively studied in hepatic injury, the role of TG7 in oxaliplatin-induced liver responses remains unclear. Oxaliplatin, a third-generation platinum chemotherapeutic, effectively treats solid tumors but can induce hepatic stress through oxidative and pro-inflammatory signaling. Adult rats received intraperitoneal oxaliplatin (10 mg/kg weekly) for 6 weeks. qRT-PCR, immunohistochemistry (IHC), immunofluorescence (IF), and a TG activity assay assessed hepatic TG7 expression, localization, and activity. Oxidative stress indicators (serum malondialdehyde [MDA] and reduced glutathione [GSH]) and pro-inflammatory cytokine transcription (CASP3, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α)) were evaluated. Oxaliplatin exposure markedly increased TG7 mRNA and protein levels, elevated TG enzymatic activity, raised MDA (+49.4%), depleted GSH (-18.6%), and upregulated CASP3, IL-6, and TNF-α. DNA fragmentation and microscopic observations from IHC- and IF-processed sections were consistent with apoptosis-associated DNA degradation and subtle stress-related structural variations. Immunostaining revealed altered TG7 distribution within hepatocytes and sinusoidal regions. In this oxaliplatin-exposed rat liver model, TG7 upregulation and increased TG activity were associated with oxidative stress, inflammatory cytokine induction, and apoptotic signaling. These findings identify TG7 as a stress-associated marker during oxaliplatin exposure and support further studies to clarify its mechanistic role and evaluate its potential as utility as a biomarker under chemotherapy-associated hepatic stress conditions.

Non-small cell lung cancer (NSCLC) continues to be the primary contributor to deaths associated with cancer. Current treatments are often limited by drug resistance and toxicity, highlighting the need for novel therapeutic approaches. Building on previous findings demonstrating that Gamabufotalin (CS-6) is effective against hepatocellular carcinoma, this study explores its mechanism of action in NSCLC. The findings indicate that CS-6 suppresses the proliferation and migratory capacity of NSCLC cells in a concentration-dependent manner, while significantly inducing apoptosis. The 48-hour half-maximal inhibitory concentration (IC50) ranged from 30 to 80 nM. In xenograft models, CS-6 effectively suppressed tumor growth (P < 0.05) without causing significant systemic toxicity at effective doses (25 mg/kg and 50 mg/kg). Mechanistically, coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2) was identified as the direct molecular target of CS-6 through Limited Proteolysis-Mass Spectrometry (LiP-MS), validated by cell thermal shift assay (CETSA), MicroScale Thermophoresis (MST), and Surface Plasmon Resonance (SPR). CHCHD2, also known as mitochondrial nuclear retrograde regulator 1 (MNRR1), is a bi-organelle regulator located primarily in the mitochondrial intermembrane space, where it controls respiratory chain stability and cristae structure, thereby regulating cell survival and apoptosis[1-3]. CHCHD2 is essential for NSCLC cell survival, as both its knockdown and overexpression reduced the efficacy of CS-6. Furthermore, transcriptomic analysis revealed that targeting CHCHD2 with CS-6 activates interferon signaling and significantly upregulates the tumor suppressor X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1). In conclusion, these findings establish the mitochondrial CHCHD2-XAF1 axis as a key mediator of CS-6 activity, thereby highlighting CS-6 as a promising candidate for targeted therapy in NSCLC.

Paracetamol and di(2-ethylhexyl) phthalate (DEHP) are endocrine-disrupting chemicals (EDCs) known to impair prenatal gonadal development and inhibit testosterone synthesis in experimental models. We hypothesized that these substances may interact with the endocannabinoid system (ECS), potentially contributing to testicular and ovarian developmental abnormalities. Pregnant Wistar rats were exposed to paracetamol (50 or 250 mg·kg⁻¹·day⁻¹) or DEHP (750 mg·kg⁻¹·day⁻¹) from gestational days 15-18. We assessed fetal testicular testosterone production, early postnatal ovarian follicle counts, and the expression of genes involved in steroidogenesis, testis descent, ovarian development, and ECS signaling, synthesis, and degradation. In a parallel in vitro approach, fetal rat testes from unexposed animals were incubated for three hours with paracetamol or its metabolite AM404, with or without the CB1 antagonist rimonabant. A separate group was exposed to MEHP, DEHP's main metabolite. In vivo, DEHP reduced anogenital distance and testicular testosterone in males, increased Cnr2 expression in both gonads, and upregulated Napepld in fetal testes. MEHP increased testosterone secretion in vitro. In ovaries, high-dose paracetamol reduced the number of healthy primordial and transitional follicles and increased atresia in primary and secondary follicles. DEHP exposure also elevated atresia in early-stage follicles. These findings suggest greater ovarian sensitivity to paracetamol compared to the testis.Unlike paracetamol, DEHP altered the expression of key ECS genes, suggesting a possible interplay between phthalates and the ECS. This raises the possibility that ECS components may be involved in the mechanisms of phthalate toxicity and could represent potential biomarkers, warranting further investigation.

To compare a non-ester methacrylate-alternative dental resin (ER) with conventional ester-based methacrylate resin (MAR) in terms of (i) susceptibility to degradation by human neutrophils (hN), (ii) influence on hN pro-inflammatory phenotypes, and (iii) modulation of Streptococcus mutans (SM) virulence-gene expression.

Endometrial cancer (EC) is a common gynecological malignancy characterized by abnormal glucose metabolism. Paeonol (Pae), a natural phenolic compound derived from traditional Chinese medicine, exhibits broad-spectrum antitumor activity. However, its role in modulating glycolysis and the underlying molecular mechanisms in EC remain poorly understood. The effects on EC cell viability (CCK-8), proliferation (EdU), apoptosis (flow cytometry), invasion (transwell), migration (wound healing), and tube formation rate were assessed. Glycolytic parameters were measured using corresponding commercial kits. Protein and mRNA expression levels were determined by Western blotting and RT-qPCR. The interaction between tripartite motif protein 26 (TRIM26) and lactate dehydrogenase A (LDHA) was investigated through co-immunoprecipitation (Co-IP), cycloheximide (CHX) chase, and ubiquitination assays. A xenograft model was established to examine the in vivo efficacy of Pae. Pae inhibited proliferation, metastasis, tube formation, and glycolysis of EC cells, and induced apoptosis. Pae suppressed EC malignant behaviors by downregulating LDHA expression. TRIM26 promoted ubiquitination-mediated degradation of LDHA. Overexpression of LDHA reversed the tumor-suppressive effects of TRIM26 overexpression in EC cells. TRIM26 knockdown attenuated the antitumor effects of Pae. In vivo experiments demonstrated that Pae inhibited tumor growth and regulated TRIM26/LDHA expression. Pae was found to promote TRIM26 expression, which in turn enhanced TRIM26-mediated ubiquitination and degradation of LDHA, thereby contributing to glycolysis inhibition and suppression of EC progression. These results suggested that Pae might exert its effects by modulating the TRIM26/LDHA axis and supported its potential therapeutic value in EC.

Microcystin-LR (MC-LR) could be largely released in water environment during the cyanobacterial blooms, endangering the health of plants, animals, and even humans. Numerous evidences had demonstrated a strong correlation between the toxicities of MC-LR and the oxidative stress induced by MC-LR. Hydrogen peroxide (H2O2) is one of the primary constituents of reactive oxygen species (ROS) and tends to be overproduced under oxidative stress. Therefore, detecting the changes in H₂O₂ levels in organisms exposed to MC-LR can serve as an indicator of MC-LR-induced oxidative damage. However, the studies of directly detecting H₂O₂ levels in organisms exposed to MC-LR are lacking. In this work, we developed a novel near-infrared probe, DSP-B, to detect H2O2 under MC-LR-induced oxidative stress in organisms. DSP-B exhibited high sensitivity and specificity to H2O2, and the detection ability of DSP-B to endogenous and exogenous H2O2 has also been validated. Then DSP-B was applied to detect the H2O2 level in cells and zebrafishes treated with MC-LR to elucidate the effect of oxidative stress caused by MC-LR. Moreover, DSP-B was utilized for tissue visualization imaging in MC-LR-poisoned loaches model, enabling the upregulation of H2O2 to be successfully observed. This study offers a novel strategy for analyzing the MC-LR-induced oxidative stress and demonstrates the potential of using probe for MC-LR toxicity research. This probe is expected to provide assistances in evaluating the risks and hazards of MC-LR exposure to organisms in the environment.

Docetaxel is the first-line chemotherapy for metastatic prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. Here we show, in an in vivo model of docetaxel resistant PC patient-derived xenografts, increased expression of genes that drive development of multiciliated cells including FOXJ1 and its effectors, many of which regulate microtubules (MTs). Mechanistically, FOXJ1 overexpression confers docetaxel resistance in vitro and in vivo, which is associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) has similar effects. Conversely, FOXJ1 knockdown impairs basal MT function, enhances taxane binding to MTs, and increases docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification is increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 is predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together, these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients who will not benefit from taxane treatment.

Fungal metabolites represent a valuable but underexplored source of anticancer agents, in part due to poorly defined mechanisms of action. Kojic acid (KA) is a fungal secondary metabolite with reported anti-melanoma activity, but its mechanism of action remains unclear. Here, we show that KA inhibits melanoma progression by disrupting MYC-driven transcriptional programs. KA treatment reduced proliferation and induced apoptosis in melanoma cells in vitro, and suppressed tumor growth in xenograft models. Transcriptomic profiling revealed a dose-dependent repression of MYC target genes, with CCNA2 and KPNA2 identified as key effectors. Both genes were validated as direct MYC targets and were associated with poor prognosis in the melanoma cohort (TCGA-SKCM). KA did not alter MYC expression but impaired its promoter binding and transcriptional activation of CCNA2 and KPNA2. Single-cell analysis further localized this axis to a proliferative mitotic subpopulation, promoting melanoma progression. These findings uncover a previously unrecognized mechanism by which KA inhibits melanoma growth and suggest that targeting the MYC-CCNA2/KPNA2 pathway may provide a therapeutic strategy for melanoma.

Advanced castration-resistant prostate cancer (CRPC) is responsive to PARP inhibitors, but only in settings of defects in homologous recombination (HR). The oncogenic M1C protein drives CRPC progression; however, it is not known if M1C plays a role in the response to PARP inhibition. The present work demonstrates that M1C is induced by olaparib treatment of HR-competent CRPC cells. As a result, M1C drives (i) ATM expression, (ii) phosphorylation of KAP1(S824) and (iii) activation of STING, which have been linked to derepression of the LINE-1 (L1) retrotransposon. In this way, M1C is necessary for induction of (i) L1-5'UTR, L1-ORF1 and L1-ORF2 transcripts and (ii) the encoded ORF1p RNA binding protein. Activation of retrotransposons induces genomic instability and drug resistance. By extension, we show that M1C also activates HERV-K102/108 gag, pol and env genes and expression of the HERV-K ENV protein. Our work further demonstrates that M1C integrates L1 and HERV-K activation with induction of APOBEC3 (A3) genes that evolved to restrain genomic instability induced by these retrotransposons. Of translational relevance, these findings demonstrate that M1C (i) is essential for inducing L1, HERV-K and A3 expression and resistance of CRPC cells to olaparib, and (ii) is a target for advancing the treatment of HR-competent CRPC with PARP inhibitors.

Elevated homocysteine (Hcy) levels are well established as an independent risk factor for atherosclerosis and its associated cardiovascular diseases. Macrophage pyroptosis- mediated inflammation plays a crucial role in the progression of atherosclerosis. Notably, glycoprotein non-metastatic melanoma protein B (GPNMB) expression is increased in macrophages within atherosclerotic plaques; however, whether GPNMB participates in Hcy-induced macrophage pyroptosis remains elusive. In the present study, we found that GPNMB expression was upregulated in Hcy- treated THP-1- derived macrophages. Consistently, serum GPNMB levels were significantly higher in patients with hyperhomocysteinemia (HHcy) compared with healthy controls. Functional experiments showed that silencing GPNMB reduced Hcy-triggered pyroptosis in THP-1-derived macrophages, whereas GPNMB overexpression exerted the opposite effect. Mechanistically, GPNMB upregulated the NOX2/NF-κB signaling pathway in THP-1-derived macrophages. Importantly, the pro-pyroptotic effect of GPNMB overexpression in Hcy-treated THP-1-derived macrophages was counteracted by either inhibition of NADPH oxidase 2 (NOX2) using the specific inhibitor gp91ds-tat or blockade of NF-κB activation with the inhibitor BAY11-7082. Moreover, serum GPNMB levels were correlated with serum Hcy levels and lipid profiles in both healthy individuals and HHcy patients. Collectively, these findings demonstrate that GPNMB facilitates Hcy-induced macrophage pyroptosis associated with the upregulation of the NOX2/NF-κB signaling pathway, highlighting the potential relevance of GPNMB as a candidate target for the clinical management of HHcy-related atherosclerotic cardiovascular disease.

Enzalutamide resistance remains a critical obstacle in the treatment of castration-resistant prostate cancer (CRPC), with potassium calcium-activated channel subfamily N member 4 (KCNN4) emerging as a key mediator of therapeutic failure. Here, we demonstrate that KCNN4 is significantly upregulated in enzalutamide-resistant PCa cells and clinical tissues, correlating with poor prognosis. Mechanistically, p300, a histone acetyltransferase, directly binds to KCNN4 and mediates its acetylation at lysine 16, which competitively inhibits ubiquitination-mediated degradation, thereby stabilizing KCNN4 protein. Notably, p300 inhibition disrupts KCNN4 acetylation, restores its proteasomal degradation, and resensitizes resistant cells to enzalutamide both in vitro and in vivo. Moreover, KCNN4 knockdown suppresses tumor growth and synergizes with enzalutamide in xenograft models, underscoring the therapeutic potential of targeting the p300-KCNN4 axis. Collectively, our findings reveal a previously unrecognized epigenetic regulatory mechanism coupling p300-mediated acetylation to potassium channel stability, providing a promising therapeutic strategy to overcome chemoresistance in advanced prostate cancer.

Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.

Arabidopsis halleri ssp. gemmifera is a promising Cd phytoremediation agent, however, the metal uptake and accumulation mechanism remain poorly understood. This study focused on the 2-hours early responses associated with Cd uptake and temporary Cd retention in roots. To distinguish Cd-specific responses from shared divalent metal responses, transcriptomic analyses were performed on roots exposed to Cd compared to excess Zn. Cd exposure induced a clearly larger number of differentially expressed genes than higher concentration of Zn exposure, indicating a distinct early response to Cd. Genes encoding transporters such as PCR2, DTX1, PDR8, PDR12, CAX4, MHX1, and ABCC2 were highly upregulated during the early exposure phase. Cd retention in roots may be mediated by these transporters, which could contribute to Cd efflux into the apoplast or vacuolar sequestration. Further, genes involved in intracellular Cd chelation, including those encoding glutathione, HIPPs, and HMPs protein, were upregulated rather than genes encoding phytochelatins. Additionally, upregulation of genes involved in cell wall biosynthesis and remodeling was observed, suggesting a structural modification occurs during early Cd exposure, contributing to reinforcement and temporary Cd storage before translocation. This hypothesis is supported by increased lignification in root tissues and the accumulation of Cd in the apoplastic region, indicating that cell wall serves as sequestration site in A. halleri.

This study explored the molecular mechanisms by which T7 peptide-modified liposomal irisin (T7@Lipo@Irisin) alleviates perioperative neurocognitive disorders (PND) via regulation of the AMPK/PGC-1α metabolic pathway. T7@Lipo@Irisin nanoparticles were prepared by thin-film hydration and ultrasonic dispersion and showed favorable physicochemical performance, with an encapsulation efficiency of approximately 85%. Serum analysis of healthy donors (n = 10) and PND patients (n = 6) showed higher IL-6 and TNF-α and lower brain-derived neurotrophic factor (BDNF) in PND. In vitro, T7@Lipo@Irisin restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) accumulation, enhanced Neuro-2a hippocampal neuron viability, and activated the AMPK/PGC-1α axis under oxidative stress. In a PND mouse model, it improved Garcia neurological scores, preserved neuronal morphology, and decreased apoptosis. Multi-omic integration of scATAC-seq/scRNA-seq and TMT-based proteomics demonstrated enhanced neuro-glial crosstalk, epigenetic activation of metabolic/antioxidant genes (e.g., Sirt1, Nfe2l2), and upregulated pathways (mitochondrial function, NAD-dependent metabolism, synaptic homeostasis). Proteomics confirmed upregulation of SIRT1, NDUFS2, and BDNF, forming a network linked to energy metabolism and neural repair. Collectively, T7@Lipo@Irisin mitigates PND by activating AMPK/PGC-1α to enhance mitochondrial function and stabilize the neuro-microenvironment.

Cucumber sex differentiation is a complex process regulated by multiple factors, including calcium (Ca2⁺) signaling. Although Ca2⁺ has been implicated in flower sex determination, its precise regulatory mechanisms remain unclear. In this study, the androecious cucumber line Banna 31-10 was treated with CaCl₂ at the shoot apices at seven-day intervals for three applications (Ca-1W, Ca-2W, Ca-3W). CaCl₂ treatment significantly increased the number of female flowers, with the effect becoming more pronounced with prolonged application. Integrated transcriptomic and metabolomic analyses revealed extensive molecular and metabolic reprogramming in response to CaCl₂. Transcription factor (TF) analysis identified 347 TFs from 56 families, with ERF, bHLH, MYB, C2H2, and MADS-box families playing key roles. Integrated transcriptome-metabolome correlation highlighted the involvement of flavonoids and plant hormone pathways, including ethylene, abscisic acid, gibberellin, cytokinin, auxin, jasmonic acid, salicylic acid, and brassinosteroid. Notably, CsACS2 and multiple calmodulin-like (CML) genes were strongly associated with hormone biosynthesis and signaling, suggesting a central role of Ca2⁺-CML-mediated regulation in female flower differentiation. Weighted gene co-expression network analysis (WGCNA) identified hub genes in co-expression modules linked to CaCl₂ response, further supporting the regulatory network underlying sex differentiation. This study provides new insights into the role of the Ca2⁺ signaling system in cucumber sex differentiation.

Aflatoxin B1 (AFB1), a known mycotoxin and environmental hazard, has been linked to breast cancer, yet the exact biological pathways remain poorly characterized. We performed a comprehensive multi-omics assessment to investigate how AFB1 may influence breast tumor biology. This encompassed transcriptomic analysis, co-expression network modeling (WGCNA), immune landscape profiling, transcription factor regulatory mapping, and spatial plus single-cell transcriptomics. Predictive biomarkers were determined through a machine learning pipeline. Twenty-two genes were identified at the intersection of AFB1-predicted targets and disease-associated expression modules. A refined panel of seven biomarkers (EGFR, MIF, MET, PPARG, MME, NQO2, NR3C2) was established through model optimization. A composite classifier using glmBoost and StepGLM achieved high discriminative accuracy (area under the curve = 0.996). SHAP interpretability indicated PPARG may act protectively, while MIF showed risk-promoting characteristics. Expression heterogeneity was observed across cell populations and spatial regions. Our integrated analytical framework offers new insights into the oncogenic potential of AFB1 in breast cancer. The identified gene set may serve as both mechanistic mediators and diagnostic markers, underscoring the value of multi-omics and machine learning approaches in environmental carcinogenesis research.

Eutrophication in plateau lakes is a major global challenge driven by excessive nitrogen (N) and phosphorus (P) inputs ; however, whether N or P is the dominant limiting nutrient remains controversial. To address this issue, we investigated the responses of Ottelia acuminata to different N and P levels using integrated physiological and transcriptomic analyses. Physiological traits and chlorophyll fluorescence parameters exhibited both synergistic and antagonistic responses to N and P treatments. N primarily regulated electron transport efficiency and light energy conversion, whereas P mainly activated photoprotective mechanisms. High P alone and combined N and P treatments inhibited genes related to photosynthetic electron transport, light-harvesting complexes, and pigment metabolism, whereas high N alone upregulated genes involved in pigments, electron transport, ATPase, and the cytochrome b6/f complex. These findings enhance understanding of eutrophication adaptation and growth in O. acuminata and provide nutrient control strategies for endangered species conservation and eutrophication management in plateau lakes.

5-Fluorouracil (5-FU) is known to cause liver injury in cancer patients. Experimental studies have reported that administration of 5-FU induces oxidative stress and inflammation in liver tissue. Ethyl gallate (EG), a plant-derived phytocompound, has been shown to possess antioxidant and anti-inflammatory properties. Therefore, in this study, we evaluated the protective effect of EG against 5-FU-induced acute liver injury in rats.

Acute lung injury (ALI) represents the most frequent complication of sepsis; however, effective drug-based interventions are still unavailable. β-sitosterol (BS) has demonstrated anti-inflammatory effects and protective properties on alveolar epithelial barriers. This study investigated the mechanism by which BS targets alveolar macrophages to attenuate sepsis-associated acute lung injury (SALI) via in vivo and in vitro experiments. Sepsis was induced in mice through cecal ligation and puncture (CLP), and BS was administered orally. An in vitro model of lipopolysaccharide (LPS)-induced MH-S cell infection validated the proposed mechanism. Macrophage polarization and mitochondrial function were assessed using flow cytometry, electron microscopy, and Western blot analysis. Results showed that BS suppressed reactive oxygen species (ROS) production and M1 macrophage polarization in LPS-stimulated MH-S cells. Mechanistically, BS promoted lysosomal degradation of dynamin-related protein 1 (DRP1) via SUMO2/3-mediated SUMOylation, preserving mitochondrial integrity and function. Transfection of MH-S cells with DRP1 plasmid abolished the BS-mediated mitochondrial protection mechanism, reducing inhibition of oxidative stress and M1 polarization. In summary, BS inhibits M1 polarization of alveolar macrophages by promoting DRP1 SUMOylation, effectively alleviating SALI in mice. These findings support BS as a potential therapeutic agent for SALI, providing a theoretical basis for clinical application.

Carya illinoinensis was a crop with high value and was widely cultivated in China. Particularly under the increasingly severe soil salinization background, the promotion of salt-tolerant C. illinoinensis varieties provided substantial economic benefits to local regions. However, the molecular mechanisms underlying C. illinoinensis's salt response remained unclear. Two-year-old C. illinoinensis saplings exhibited significant damage after treatment with 600 mM NaCl solution. Transcriptome data at nine salt treatment time points were obtained from two-year-old C. illinoinensis saplings using RNA-seq, and 7840 differentially expressed genes (DEGs) were identified to construct a time-ordered gene co-expression network (TO-GCN). DEGs in the TO-GCN were classified into 10 levels corresponding to salt treatment time points. Genes in Level 1 (L1) and Level 2 (L2) were enriched in Gene Ontology (GO) terms associated with photosynthesis and transport channel proteins. Cluster analysis identified three aquaporin-coding genes among highly expressed genes. Based on promoter cis-acting elements, A/T-rich sequence features, and antagonistic gene expression patterns in transcriptomic data, it was speculated that CiPIP2;8 might be transcriptionally repressed by the upstream transcription factor CiPLATZ23. This hypothesis was validated through a Dual-luciferase reporter (DLR) assay. The presence of ABA-responsive elements (ABREs) in ProCiPLATZ23 suggested its involvement in the abscisic acid (ABA) pathway. Transient expression of ProCiPLATZ23::GUS in Nicotiana benthamiana exhibited enhanced histochemical staining following ABA treatment. Within 24 h after spraying walnuts with ABA, the transcription level of CiPLATZ23 rapidly increased. Furthermore, 35S::CiPLATZ23 overexpression lines in Arabidopsis thaliana displayed reduced ABA sensitivity compared to Wild-type (WT) A. thaliana. Reverse transcription quantitative PCR (RT-qPCR), yeast one-hybrid, and DLR assays confirmed that CiPLATZ23 participated in regulating ABA sensitivity by binding to the promoter of AtPIP2;8, the homolog of CiPIP2;8 in A. thaliana. Characterization of canonical ABA pathway families confirmed that C. illinoinensis ABA responses were implicated under salt stress. This study employed TO-GCN analysis of RNA-seq data to elucidate salt stress response mechanisms in C. illinoinensis and identified a key module 'CiPLATZ23-PIP2; 8' that may be associated with ABA.