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Recent large-scale studies, including a longitudinal study spanning 24 years (Swedish Obese Subjects), have demonstrated that weight loss in obese patients is directly correlated with reduced metabolic complications and mortality. Nonetheless, instances of weight regain and subsequent loss of metabolic improvements have been observed in some patients, with adipose tissue dysfunction and fibrosis identified as significant contributing factors. Adipose tissue fibrosis is increasingly recognized as a critical pathological mechanism that influences weight loss responsiveness and long-term prognosis, extending beyond the previously predominant focus on inflammatory responses. Recent advancements in spatial transcriptomics and single-cell omics have elucidated the interactions and molecular networks among various cell types (e.g., fibroblasts and macrophages), revealing the involvement of miRNAs, among other factors, in metabolic plasticity and weight maintenance. Anti-diabetic therapies (such as GLP-1 receptor agonists, SGLT2 inhibitors, and thiazolidinediones) and bariatric surgery have been shown to contribute to tissue remodeling and the mitigation of fibrosis. However, the issue of weight regain upon drug discontinuation persists, underscoring the necessity for integrated strategies that simultaneously target adipose tissue set-point regulation and fibrosis improvement. In conclusion, adipose tissue fibrosis is proposed as a novel predictive and therapeutic target for metabolic health prognosis and treatment selection in patients with obesity. 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