Breast cancer is the most common malignancy among women worldwide, with drug therapy playing a crucial role in its treatment. In recent years, poly ADP-ribose polymerase (PARP) inhibitors, such as Olaparib, have shown significant efficacy in the management of BReast CAncer gene (BRCA)-mutated breast cancers. However, the emergence of resistance has become a major clinical challenge, limiting their long-term effectiveness. This in-silico study aimed to identify key genes associated with Olaparib resistance through comprehensive bioinformatics analysis. Differential expression and drug sensitivity prediction were performed to identify resistance-associated genes, followed by pathway enrichment and protein–protein interaction (PPI) network construction. Kaplan–Meier survival analysis and Cox regression were conducted to evaluate the prognostic value of candidate genes. Four immune-related genes—CD19, CXCL9, ICOS, and CXCL13—were identified as being closely associated with Olaparib resistance and relapse-free survival. Additionally, comparative drug sensitivity analysis revealed that high-risk subgroups may exhibit differential response patterns to specific chemotherapeutic agents. These findings provide a theoretical framework for understanding the molecular basis of Olaparib resistance in breast cancer and offer insights for future experimental and translational research.

Resistance to poly ADP-ribose polymerase (PARP) inhibitors has emerged as a major obstacle to durable clinical benefit in breast cancer. While multiple preclinical strategies have been proposed, there is a lack of translational frameworks that prioritize interventions based on mechanistic robustness, biomarker relevance, and strength of evidence. We performed a systematic and evidence-informed synthesis of 22 preclinical studies investigating therapeutic approaches to overcome PARP inhibitor resistance. Studies were evaluated across experimental models, mechanistic endpoints, and therapeutic outcomes. Risk of bias was assessed using the SYRCLE and ROBINS-I tools, and the consistency and certainty of evidence were appraised using the GRADE framework to support translational prioritization. Epigenetic targeting via EZH2 inhibition and immune microenvironment modulation through STING pathway activation consistently demonstrated high-quality evidence for tumor suppression, survival benefit, and immunologic activation in BRCA1-mutant models. In contrast, strategies aimed at restoring homologous recombination exhibited strong in vitro synergy but limited in vivo translatability, underscoring pharmacokinetic and model-dependent constraints. This review advances an evidence-based translational prioritization framework to guide the clinical development of combination strategies for PARP inhibitor-resistant breast cancer. We identify critical gaps in biomarker integration, standardized resistance modeling-particularly in BRCA wild-type disease-and dynamic monitoring of resistance evolution, and propose key directions for future preclinical and early-phase clinical research.

Background: Chemotherapy resistance remains a major obstacle in breast cancer treatment, particularly in triple-negative breast cancer (TNBC). Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a potential therapeutic vulnerability in drug-resistant cancers, but preclinical evidence lacks systematic synthesis. Methods: PubMed, Scopus, Embase and Web of Science were systematically searched for original studies published between January 2016 and May 2026 investigating ferroptosis in chemotherapy-resistant breast cancer models. Study characteristics, mechanistic data, and outcomes were extracted. Methodological quality was assessed using SYRCLE ( in vivo ) and adapted OHAT ( in vitro ) tools. A narrative synthesis and evidence strength ranking system (Levels A-C) were developed based on study number, in vivo validation, and drug class coverage. Results: Forty−four studies met inclusion criteria, with the majority published since 2024. TNBC was the focus of 47.7% of studies. Mechanisms were classified into six categories: GPX4 axis (28 studies, 63.6%), iron metabolism regulation (8 studies, 18.2%), SLC7A11/xCT pathway (5 studies, 11.4%), and three single−study mechanisms (6.8% combined). GPX4 modulation demonstrated efficacy across all drug classes. Evidence ranking classified the GPX4 axis, iron metabolism regulation, and the SLC7A11/xCT pathway as Level A (strong evidence), and the remaining mechanisms as Level C. Methodological quality was adequate: 88.6% performed rescue experiments, 79.5% included in vivo validation. However, reporting of randomization (11.4%) and blinding (0%) in animal studies requires improvement. Conclusion: Ferroptosis regulation represents a mechanistically diverse and promising strategy to overcome breast cancer chemoresistance. The GPX4 axis, iron metabolism regulation, and the SLC7A11/xCT pathway are the most consistently supported mechanisms, providing a framework for prioritizing translational targets. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261334827.

Resistance to poly ADP-ribose polymerase (PARP) inhibitors limits durable clinical benefit in breast cancer. The translational relevance of resistance-asso