Liver Injury Research Articles

Macrophage miR-4524a-5p/TBP promotes β-TrCP -TIM3 complex activation and TGFβ release and aggravates NAFLD-associated fibrosis

Macrophages hold a critical position in maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. TIM3 is a promising protector in MCD-induced steatohepatitis in acute liver injury. However, we recently find TIM3 as a driver of fibrosis in MCD/HFD-induced chronic liver injury. This study aims to explore how macrophage TIM3 drivers NAFLD-associated chronic liver injury as well as identify a subtype of fibrotic patients suitable for anti-TIM3 immunotherapy. Here, we found that TIM3 was highly expressed in liver macrophages in a long-term MCD- or HFD-fed mice with fibrotic NASH. Elevated β-TrCP in macrophages promoted TIM3 polyubiquitination and membrane translocation. The ubiquitinated TIM3 then bound with PI3K and followed by inhibition of mTOR and activation of macrophage M2 polarization and TGF-β release, leading to HSC activation and liver fibrosis. Furthermore, elevated TIM3 was attributed to the transcriptional TBP upregulation and miR-4524a-5p downregulation. Targeting of TIM3 significantly attenuated liver fibrosis in mice. In clinical NASH patients, elevated macrophage TIM3 is positively correlated with TBP expression and negatively associated with miR-4524a-5p. Decreased miR-4524a-5p in plasma was a biomarker for the NASH fibrosis patients suitable for anti-TIM3 therapy. In conclusion, this study reveals that miR-4524a-5p/TBP promotes β-TrCP/TIM3 complex activation in macrophages and aggravates chronic NASH fibrosis, providing miR-4524a-5p as an effective blood biomarker for a subtype of chronic NASH patients with fibrosis suitable for anti-TIM3 treatment.

Retrospective analysis of clinical features of liver injury induced by levofloxacin

ABSTRACT Background Current understanding of the relationship between levofloxacin exposure and hepatic injury primarily relies on case reports. This article aims to investigate the features of levofloxacin-induced liver injury. Research design and methods We incorporated case series and reports regarding levofloxacin-induced hepatotoxicity published prior to 30 June 2024, utilizing an extensive search database. The data from 40 patients were collected and subjected to descriptive analysis. Results The median age of the 40 patients was 60 years (range 10, 99), and the median time to exacerbation was 5 days (range 1 199). Liver injury was categorized as hepatocellular (62.5%), cholestatic (12.5%), and mixed (25.0%). Clinical manifestations included asymptomatic elevations in liver enzymes, jaundice, dark urine, nausea, vomiting, anorexia, hepatic encephalopathy. Laboratory evaluations revealed varying degrees of elevation in aminotransferases and total bilirubin. Biopsy results indicated hepatic necrosis, cholestasis, steatosis, and inflammatory infiltrates. After levofloxacin discontinuation, the median time to normalization of liver function was 21 days (range 3, 103), and 8 patients ultimately succumbing to the condition. Conclusions Hepatotoxicity is an uncommon but severe adverse effect associated with levofloxacin. Immediate discontinuation of levofloxacin is warranted if there is a rapid increase in aminotransferase levels or the emergence of hepatitis symptoms.

Reprogramming Glucose Metabolism of Macrophage for Acute Liver Failure Therapy with Itaconate Lipo-Nanodrug.

Acute liver failure (ALF) is a life-threatening disease featuring comprehensive inflammatory response and metabolic disorders in which macrophages exert central roles. A glucose metabolism mediator of macrophages, itaconate, has demonstrated potent anti-inflammatory efficacy in various diseases, implying that itaconate could work in treating ALF. However, systemic administration of itaconate may lead to immune disorder, making targeting the delivery of itaconate to the liver lesion area highly important. Herein, a liposomal nanodrug incorporating itaconate is developed, and its potential in treating acute liver failure in an ALF murine model established by LPS/D-GalN administration is tested. The nanodrug shows preferential liver accumulation to effectively alleviate LPS/D-GalN-induced hepatic histopathological injury by decreasing oxidative stress. Moreover, it reprograms the glucose metabolism of macrophages, resulting in macrophage repolarization toward the anti-inflammatory phenotype. Furthermore, western-blot and immunohistochemical assays verifies that the nanodrug may inhibit aerobic glycolysis of macrophages in an NRF2 and STING-dependent manner. These results underline the promise of the nanodrug for ALF treatment by reprogramming glucose metabolism.

In Vivo Inhibition of CYP2E1 Fails to Reduce Pulegone-induced Liver Injury in Mice

In Vivo Inhibition of CYP2E1 Fails to Reduce Pulegone-induced Liver Injury in Mice

TJ0113 attenuates fibrosis in metabolic dysfunction-associated steatohepatitis by inducing mitophagy.

TJ0113 attenuates fibrosis in metabolic dysfunction-associated steatohepatitis by inducing mitophagy.

Ferroptosis as a key player in the pathogenesis and intervention therapy in liver injury: focusing on drug-induced hepatotoxicity.

Globally, drug-induced hepatotoxicity or drug-induced liver injury (DILI) is a serious clinical concern. Knowing the processes and patterns of cell death is essential for finding new therapeutic targets since there are not many alternatives to therapy for severe liver lesions. Excessive lipid peroxidation is a hallmark of ferroptosis, an iron-reliant non-apoptotic cell death linked to various liver pathologies. When iron is pathogenic, concomitant inflammation may exacerbate iron-mediated liver injury, and the hepatocyte necrosis that results is a key element in the fibrogenic response. The idea that dysregulated metabolic pathways and compromised iron homeostasis contribute to the development of liver injury by ferroptosis is being supported by new data. Various ferroptosis-linked genes and pathways have been linked to liver injury, although the molecular processes behind ferroptosis's pathogenicity are not well known. Here, we delve into the features of ferroptosis, the processes governing ferroptosis, and our current knowledge of iron metabolism. We also provide an overview of ferroptosis's involvement in the pathophysiology of liver injury, particularly DILI. Lastly, the therapeutic possibilities of ferroptosis targeting for liver injury management have been provided. Natural products, nanoparticles (NPs), mesenchymal stem cell (MSC), and their exosomes have attracted increasing attention among such therapeutics.

Multicomponent parenteral lipid emulsions do not prevent liver injury in neonatal pigs with obstructive cholestasis.

Biliary atresia (BA) is a pediatric liver disease that often necessitates parenteral nutrition (PN) to support growth due to impaired liver function. While soy oil lipid emulsions (SLE) are commonly used in PN, they may contribute to cholestatic liver injury. In contrast, mixed oil lipid emulsions (MLE) show promise in preventing cholestasis in non-BA infants, potentially by restoring bile flow. However, their effectiveness in cases of complete bile duct obstruction, as seen in BA, remains uncertain. To explore the potential benefits of MLE in BA, we utilized a neonatal pig model of bile duct ligation (BDL). Pigs underwent either BDL or sham surgery and were subsequently fed either MLE or SLE via PN, or enterally with formula. The MLE-BDL pigs exhibited significantly greater weight gain compared to those fed SLE or formula enterally. Additionally, MLE-BDL pigs showed higher serum bile acid and gamma-glutamyl transferase concentrations compared to SLE-BDL pigs. However, no significant differences in liver injury, assessed by ductular reaction or fibrosis, were observed between MLE- and SLE-BDL pigs. Based on weight gain alone, MLE may be a superior lipid emulsion for use in neonates with obstructive cholestasis.

Chronic intermittent hypoxia alleviates alcohol-related liver injury via downregulation of hepatic hypoxia-inducible factor-2α.

Alcohol-related liver disease (ALD) is one of the leading causes of alcohol-related morbidity and mortality worldwide. Unfortunately, limited therapeutic options are currently available, due to the complex risk factors involved as well as the lack of information on the molecular mechanisms driving its progression. Interestingly, chronic, excessive alcohol intake has been reported to exacerbate the severity of Obstructive sleep apnea (OSA), a respiratory disorder typically characterized by chronic intermittent hypoxia (CIH). However, this relationship between alcohol-enhanced OSA and ALD development/progression remains to be elucidated. As an approach to investigate this relationship in vivo Gao-binge ALD and CIH mouse models were established. Alcohol-related liver injury, hepatic steatosis, inflammation and oxidative stress were then assessed in these models. In addition, LPS and ethanol-co-treated AML12 hepatocytes served as an in vitro model to investigate the mechanisms through which CIH affects ethanol-induced liver injury. CIH intervention ameliorated alcohol-related liver injury, reduced hepatic lipid accumulation and oxidative stress and alleviated liver inflammation. Mechanistically, in the liver of these Gao-binge mice, CIH intervention inhibited alcohol-induced upregulation and activation of hypoxia-inducible factor 2α (HIF-2α), a protein which plays a key role in hepatic lipid metabolism and liver injury. Similar to these effects observed in response to CIH intervention, treatment of Gao-binge mice with the selective inhibitor of HIF-2α, PT2385, alleviated alcohol-related liver injury and steatosis while inhibiting oxidative stress and inflammation. Additional findings from our in vitro model revealed that CIH downregulated HIF-2α by promoting calpains protein expression, thereby reducing the accumulation of lipid droplets and decreasing ROS production in AML12 cells co-challenged with LPS and ethanol. The above results provide important, new evidence that re-conceptualizes the role of alcohol-enhanced OSA in ALD progression. Moreover, these findings can serve as the foundation for the development of HIF-2α inhibitors for use in the prevention and treatment of ALD.

Liver organoids uncover tire-derived 6-PPDQ-induced hepatotoxicity of: A preliminary application of environmental toxicology and safety assessment.

Liver organoids uncover tire-derived 6-PPDQ-induced hepatotoxicity of: A preliminary application of environmental toxicology and safety assessment.

Oryzanol Ameliorates MCD-Induced Metabolic dysfunction-associated Steatohepatitis in Mice via Gut Microbiota Reprogramming and TLR4/NF-κB Signaling Suppression.

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major global health concern that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as key mechanistic pathways in MASH development. Oryzanol (ORY), rice bran bioactive compound, exhibits antioxidant, anti inflammatory, hypolipidemic and hypoglycemic properties. Here, we investigated the potential of ORY in alleviating MASH and its association with gut microbiota and MASH progression. Methods: Male C57BL/6J mice were fed normal chow diet or methionine-choline-deficient diet and received ORY supplementation at 300 mg/kg/day via gavage for 4 weeks. Liver injury, inflammation, lipid accumulation and TLR4/NF-κB Signaling protein levels were assessed. Additionally, changes in gut microbiota diversity and abundance across groups were evaluated using 16S rDNA sequencing. Results: Our results demonstrated that ORY significantly reduced lipid accumulation and liver enzymes, ameliorated liver and ileum damage, and restored intestinal barrier function in MASH mice. Furthermore, ORY decreased plasma LPS levels, inflammatory cytokines and downregulated TLR4, MyD88, and NF-κB protein levels in the liver. ORY enhanced tight junction protein level (ZO-1, occludin) in the gut. Microbial analysis revealed that ORY positively impacted Firmicutes and Bacteroidetes abundance, promoted beneficial bacteria like Lactobacillus and Lachnospiraceae_NK4A136_group, and inhibited harmful bacteria such as Mucispirillum, Bacteroides, and Colidextribacter. Notably, ORY increased Akkermansia abundance, potentially modulating metabolic and inflammatory pathways. Conclusion: ORY exerted restorative and reversible effects on the pathophysiological damage within gut-liver axis in MASH mice. The therapeutic mechanism may be related to the modulation of the gut microbiota and TLR4/NF-κB signaling pathway.

Investigating Network and Experimental Effect of Silibinin on Lipin-1 and Lipin-2 Gene Expression during Ischemia-reperfusion of the Liver in Rats.

This study aims to investigate the impact of silibinin (SILI) on the expression of the Lipin-1 and Lipin-2 genes during warm ischemia-reperfusion (I/R) of the liver. Network pharmacology was employed to identify potential targets of SILI in the context of liver inflammation and to elucidate the mechanism underlying the regulation of Lipin gene expression. The rats were allocated into four groups, each comprising eight individuals: vehicle group: These rats underwent a median laparotomy, and were administered normal saline. (2) SILI group: Rats in this group received 50 mg/kg of SILI after laparotomy. (3) I/R group: Rats in this group experienced I/R and were administered normal saline. (4) I/R+SILI group: In this group, rats were treated with SILI in conjunction with the I/R procedure. Western and real-time PCR were used to measure protein levels, and assess Lipin-1 and Lipin-2 gene expression. The analysis identified 18 shared targets between SILI (Severe Acute Liver Injury) and liver inflammation, linking them to 107 KEGG pathways, with the mTOR signaling pathway standing out as a critical connection to Lipin. Docking studies of targets in the mTOR signaling pathway revealed binding energies of -9.7 kcal/mol for PIK3CA and -10.4 kcal/mol for mTOR protein. Furthermore, the protein level and gene expression of Lipin-1 and Lipin-2 genes were significantly elevated during I/R compared to the vehicle group (P < 0.001). However, SILI was observed to reduce their expression during I/R (P < 0.05). The beneficial effects of SILI can be attributed to the modulation of Lipin-1 and Lipin-2 gene expression during I/R, which is likely one of the mechanisms underlying its beneficial effects during I/R.

Luteolin Relieves Metabolic Dysfunction-Associated Fatty Liver Disease Caused by a High-Fat Diet in Rats Through Modulating the AdipoR1/AMPK/PPARγ Signaling Pathway

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant global public health issue. Luteolin possesses several beneficial biological properties, including antioxidation and anti-inflammation. This study investigated luteolin’s effect and potential mechanisms on MAFLD in high-fat diet (HFD)-fed rats. Rats were administered an HFD supplemented with fructose for 12 weeks to induce MAFLD. After that, the HFD-fed rats were given either luteolin (50 or 100 mg/kg/day) or metformin (100 mg/kg/day) for 4 weeks. Luteolin improved metabolic parameters induced by the HFD, since it decreased body weight, blood pressure, fasting blood glucose, serum insulin, free fatty acids, cholesterol, and triglyceride levels (p &lt; 0.05). Luteolin reduced hepatic injury and inflammatory markers in HFD-fed rats (p &lt; 0.05). Additionally, HFD-fed rats treated with luteolin showed reduced malondialdehyde and raised catalase activity in plasma (p &lt; 0.05). Luteolin attenuated hepatic steatosis compared to the untreated rats (p &lt; 0.05). Luteolin also increased plasma adiponectin levels accompanied by upregulation of adiponectin receptor 1 (AdipoR1), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ (PPAR-γ) protein expression in liver (p &lt; 0.05). These findings revealed that luteolin ameliorated HFD-induced MAFLD in rats, possibly by reducing metabolic alterations and oxidative stress and restoring AdipoR1, AMPK, and PPARγ protein expression in HFD-fed rats.

The DHCR7 is the key target of lipotoxic liver injury caused by matrine through abnormal activation of the cholesterol synthesis pathway.

The DHCR7 is the key target of lipotoxic liver injury caused by matrine through abnormal activation of the cholesterol synthesis pathway.

DUBA sustains the stability of NOD2 and RIPK2 to enhance innate immune responses.

Nucleotide-binding oligomerization domain containing 2 (NOD2) detects conserved fragments of bacterial peptidoglycan in the cytosol and induces innate immune responses. Here, we found that the NOD2 signaling pathway was critically regulated by the deubiquitinating enzyme DUBA. DUBA-deficient macrophages were defective in NOD2 signaling and produced significantly lower amounts of cytokines and chemokines in response to muramyl dipeptide (MDP). DUBA potentiated NOD2-mediated signal transduction by maintaining the protein levels of NOD2 and receptor-interacting protein kinase 2 (RIPK2). Mechanistically, DUBA interacted with NOD2 and RIPK2 and removed K48-linked polyubiquitin chains from them through enzymatic activity, thereby inhibiting the proteasomal degradation of NOD2 and RIPK2. Macrophage-specific ablation of DUBA attenuated MDP-induced systematic inflammation and liver injury in mice. In addition, DUBA deficiency in macrophages rendered mice hypersensitive to DSS-induced colitis and eliminated the protective effect of MDP treatment in colitis. Thus, DUBA acts as an important regulator of NOD2-mediated signaling and innate immune responses.

Inhibition of colorectal cancer cell growth by downregulation of M2-PK and reduction of aerobic glycolysis by clove active ingredients

Exploring the anti-tumor molecular mechanisms of traditional Chinese medicines has become an important strategy to develop novel anti-tumor drugs in the clinic. Several pharmacological studies have reported the antioxidant, antibacterial, anti-inflammatory, and anti-tumor effects of clove. Previously, we have shown that the active fraction from clove (AFC) can inhibit the growth of tumor cells, particularly colon cancer cells, in vitro. However, the mechanism of action regarding the anti-colon cancer activity of AFC, especially in aerobic glycolysis, has not been adequately investigated. In this study, we found that AFC significantly inhibited the growth of five types of colon cancer cells, downregulated the mRNA and protein levels of M2-type pyruvate kinase (PKM2), and reduced aerobic glycolysis capacity. Transfection of PKM2-siRNA mimicked the inhibitory effects of AFC on aerobic glycolysis in colon cancer cells. Furthermore, the highly expressed, tumor-specific targets c-myc and cyclin D1 in cells were also found to be downregulated following the action of AFC. In the HCT116 cell xenograft nude mice models, the results after AFC administration were consistent with those of the cellular experiments, while AFC caused less liver injury and weight loss than the conventional chemotherapeutic agent 5- fluorouracil (5-FU). In conclusion, AFC inhibits colon cancer growth by downregulating PKM2 to inhibit aerobic glycolysis and reduce the tumor-specific high expression of c-myc and cyclin D1. Future work should explore how it downregulates pyruvate kinase (PK) in the first place, along with the intrinsic mechanism between the downregulation of PKM2 and the downregulation of c-myc.

Surgical management of injuries to the abdomen in patients with multiple and/or severe trauma– a systematic review and clinical practice guideline update

PurposeOur aim was to update evidence-based and consensus-based recommendations for the surgical management of abdominal injuries in patients with multiple and/or severe injuries based on current evidence. This guideline topic is part of the 2022 update of the German Guideline on the Treatment of Patients with Multiple and/or Severe Injuries.MethodsMEDLINE and Embase were systematically searched to May 2021. Further literature reports were obtained from clinical experts. Randomised controlled trials, prospective cohort studies, cross-sectional studies and comparative registry studies were included if they compared interventions for the surgical management of abdominal injuries in patients with multiple and/or severe injuries. We considered patient-relevant clinical outcomes such as mortality, length of stay, and diagnostic test accuracy. Risk of bias was assessed using NICE 2012 checklists. The evidence was synthesised narratively, and expert consensus was used to develop recommendations and determine their strength.ResultsThree studies were identified. The topics of these studies were nonoperative management in haemodynamically stable patients with isolated blunt hepatic (n = 1) or splenic injuries (n = 1) and selective angioembolisation (n = 1). None of the recommendations were modified, one new recommendation was developed, and one was deleted based on the updated evidence and expert consensus. All recommendations achieved strong consensus.ConclusionThe following recommendations are made. All but one of the previous guideline recommendations were confirmed. The recommendation to perform diagnostic peritoneal lavage in exceptional cases was completely deleted. An additional recommendation was made and states that the performance of a diagnostic laparoscopy can be considered in haemodynamically stable patients with penetrating trauma when there is therapeutic uncertainty.

Protective Effect of Dictyophora rubrovolvata Extract on Intestinal and Liver Tissue Toxicity Induced by Metformin Disinfection Byproducts

Metformin disinfection byproducts Y and C have emerged as pollutants of concern in drinking water systems and are suspected to possess significant toxicity to mammals. However, effective strategies to mitigate the effects of Y and C exposure in mammals have not been thoroughly formulated. This study aimed to investigate the toxicity and characteristic phenotypes of short-term, high-dose exposure to Y and C in the intestine and liver of mice and to evaluate the protective effects of Dictyophora rubrovolvata extract (DRE) on Y- and C-induced intestinal and liver damage. The results showed that exposure-induced intestinal toxicity manifested mainly as intestinal barrier dysfunction, induction of immune response and oxidative stress, and disruption of intestinal flora homeostasis. Hepatotoxicity was mainly characterized by histopathological changes such as vacuolar degeneration, abnormal liver function, and oxidative stress. Additionally, marked changes in gut microbiota and biochemical indicators were closely related to hepatic and intestinal injuries after exposure. DRE effectively alleviated Y- and C-induced intestinal and liver damage, reshaped the gut microbiota, and maintained gut‒liver axis homeostasis. These findings provide new insights into the toxic effects of disinfection byproduct exposure through the gut-liver axis and suggest that functional food extracts may serve to protect against these adverse health outcomes.

Histone methyltransferase SMYD2 regulates the activation of hepatic stellate cells by activating TLR4 signaling

Liver fibrosis represents a pathological outcome in the progression of chronic liver diseases, primarily driven by the activation of hepatic stellate cells (HSCs) induced by various chronic liver injury factors. Substantial evidence indicates that under inflammatory conditions, aberrant activation of HSCs leads to excessive deposition of extracellular matrix (ECM). Therefore, identifying novel molecular targets to inhibit HSCs activation and proliferation is of significant clinical importance for the prevention and treatment of liver fibrosis. SMYD2 (SET and MYND domain containing 2) is a histone methyltransferase primarily responsible for catalyzing the methylation of lysine 36 on histone H3 (H3K36). However, the specific role and mechanisms of SMYD2 in the progression of liver fibrosis remain poorly understood. Thus, this study aims to systematically investigate the molecular regulatory mechanisms of SMYD2 in the development of liver fibrosis. Our findings demonstrate that both SMYD2 and its catalytic product, H3K36me2, are significantly upregulated in carbon tetrachloride (CCl4)-induced liver fibrosis tissues in mice and during the spontaneous activation of primary mouse HSCs in vitro. Knockdown of SMYD2 expression significantly reduces H3K36me2 modification levels and effectively inhibits transforming growth factor-β1 (TGF-β1)-induced HSC activation. Further mechanistic studies reveal that the toll-like receptor 4 (TLR4) -nuclear factor kappa-B(NF-κB) signaling pathway is involved in this regulatory process, where Smyd2 positively regulates Tlr4 gene expression by modulating H3K36me2 modification levels. These findings suggest that SMYD2 may serve as a potential therapeutic target for liver fibrosis, warranting further exploration in subsequent clinical translational research.

BoostDILI: Extreme Gradient Boost-Powered Drug-Induced Liver Injury Prediction and Structural Alerts Generation.

Over the past 60 years, drug-induced liver injury (DILI) has played a key role in the withdrawal of marketed drugs due to safety concerns. Early prediction of DILI is crucial for developing safer pharmaceuticals, yet current in vitro and in vivo testing methods are complex and cumbersome. In this study, we developed an extreme gradient boosting (XGB)-powered machine learning (ML) model for DILI prediction. Comparing various DILI prediction models is challenging because they rely on different public data sets. We comprehensively evaluated the proposed BoostDILI model to address two crucial questions: 1. Can insights derived from public data sets help in DILI prediction for Food and Drug Administration (FDA) approved drugs? 2. Can we generate structural alerts to improve the model's explainability? To address the first question, we developed a DILI prediction model using four publicly available data sets. This effort led to the creation of the BoostDILI model, which achieved a 5-fold CV accuracy of 0.70. A sequential feature selection method was employed to identify relevant descriptors. This model integrates feature-level representations derived from RDKit (12 features) and Mordred (23 features) features. Bayesian statistics was applied to identify high-performance substructures iteratively, and a structural alerts model was developed to address the second question. The developed model was further validated with two FDA-approved drug data sets, DILIst and DILIRank. The BoostDILI model offers a trustable solution for evaluating the DILI risk in preclinical research. The structural alerts help in identifying the substructures that may be responsible for DILI. The data set and the source code are available at https://github.com/Naga270588/BoostDILI.

How early life trauma influences youth resilience: the buffering effect of kinship in promoting good health and well-being

ABSTRACT Early life experiences, including physical, emotional, and neglectful abuse, are associated with various aspects of a child’s development and mental health. This study examined the relationship between early life trauma and youth resilience and further explored the potential mediating role of sibling relationships in this association. A purposive sample of 300 youth, comprised of an equal number of girls (n = 150) and boys (n = 150), was drawn from private and public educational institutes, mainly from Rawalpindi district. Age range of the participants was 13 to 18. Three standardized scales including short form of Childhood Trauma Questionnaire, Brief Resilience Scale and Sibling Relationship Questionnaire were used for data collection. Findings from this study highlighted the significant negative relationship between early life trauma and resilience. Further correlation analysis indicated that sibling relationships were negatively associated with resilience. Linear regression analysis revealed that sibling relationship emerged as a negative predictor of resilience. Significant gender differences were found in terms of early life trauma among youth. Mediation analysis was carried out with PROCESS macro for SPSS which revealed a mediating role of sibling relationship in relation between early life trauma and resilience. Furthermore, it was found that youth from upper-middleclass were more exposed to early life trauma than middle and lower-middle class. Furthermore, analysis showed that youth from upper-middle class have strong sibling bonds than lower middle-class families. However, results indicated that youth from lower-middle socioeconomic status are more resilient than youth from upper-middle class. This study would benefit parents, therapists, counselors and researchers to get in-depth understanding of the phenomenon. Further, it would help therapists to integrate family-based approaches to strengthen sibling bonds and help them to design early childhood programs to support healthy development and prevent maltreatment.