The results of the present study suggest that RA-FLS may use the autophagic pathway in which HMGB1 and Beclin-1 (but not the Akt/mTOR pathway) are involved as a survival mechanism to evade the perturbations of cellular biosynthetic processes by the antimetabolite MTX to sustain cell viability in conditions of metabolic stress. This evidence concerns the gene BECN1 and rheumatoid arthritis.